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Bonet IJM, Araldi D, Khomula EV, Bogen O, Green PG, Levine JD. G-protein-coupled estrogen receptor 30 regulation of signaling downstream of protein kinase Cε mediates sex dimorphism in hyaluronan-induced antihyperalgesia. Pain 2025; 166:539-556. [PMID: 39787533 PMCID: PMC11810595 DOI: 10.1097/j.pain.0000000000003419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Accepted: 07/12/2024] [Indexed: 01/12/2025]
Abstract
ABSTRACT High molecular weight hyaluronan (HMWH) inhibits hyperalgesia induced by diverse pronociceptive inflammatory mediators and their second messengers, in rats of both sexes. However, the hyperalgesia induced by ligands at 3 pattern recognition receptors, lipopolysaccharide (a toll-like receptor 4 agonist), lipoteichoic acid (a toll-like receptor 2/6 agonist), and nigericin (a NOD-like receptor family, pyrin domain containing 3 activator), and oxaliplatin and paclitaxel chemotherapy-induced peripheral neuropathy are only attenuated in males. After gonadectomy or intrathecal administration of an antisense to G-protein-coupled estrogen receptor 30 (GPER) mRNA, HMWH produces antihyperalgesia in females. In nociceptors cultured from rats that had been treated with oxaliplatin, HMWH reverses nociceptor sensitization from male and GPER antisense-treated female, but not from gonad intact females. G-protein-coupled estrogen receptor-dependent sex dimorphism for HMWH-induced antihyperalgesia was also observed for the prolongation of prostaglandin E 2 (PGE 2 )-induced hyperalgesia in primed nociceptors. While in primed rats, HMWH inhibits early, protein kinase A-dependent hyperalgesia, 30 minutes post PGE 2 injection, in both sexes; measured 4 hours post-PGE 2 , HMWH inhibits the protein kinase Cε (PKCε)-dependent prolongation of PGE 2 hyperalgesia only in males and GPER antisense-treated females. In females, hyperalgesia induced by PKCε agonist, ψεRACK, in control but not in primed nociceptors, was inhibited by HMWH. Inhibitors of 2 GPER second messengers, extracellular-regulated kinase 1/2 and nonreceptor tyrosine kinase, also unmasked HMWH antihyperalgesia in females with oxaliplatin chemotherapy-induced peripheral neuropathy, a condition in which nociceptors are primed as well as sensitized. Our results support GPER-dependent sex dimorphism in HMWH-induced antihyperalgesia for pain induced by pattern recognition receptor agonists, and chronic inflammatory and neuropathic pain, mediated by changes in signaling downstream of PKCε in primed nociceptors.
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Affiliation(s)
- Ivan J. M. Bonet
- Department of Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Dionéia Araldi
- Department of Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Eugen V. Khomula
- Department of Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Oliver Bogen
- Department of Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Paul G. Green
- Department of Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
- Departments of Preventative & Restorative Dental Sciences and Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Jon D. Levine
- Department of Oral & Maxillofacial Surgery, and Division of Neuroscience, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
- Departments of Medicine and Oral & Maxillofacial Surgery, and Division of Neuroscience, UCSF Pain and Addiction Research Center, University of California at San Francisco, 513 Parnassus Avenue, San Francisco, CA 94143, USA
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Kan YY, Chang YS, Liao WC, Chao TN, Hsieh YL. Roles of Neuronal Protein Kinase Cε on Endoplasmic Reticulum Stress and Autophagic Formation in Diabetic Neuropathy. Mol Neurobiol 2024; 61:2481-2495. [PMID: 37906389 PMCID: PMC11043183 DOI: 10.1007/s12035-023-03716-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2023] [Accepted: 10/14/2023] [Indexed: 11/02/2023]
Abstract
In chronic diabetic neuropathy (DN), the cellular mechanisms of neuropathic pain remain unclear. Protein kinase C epsilon (PKCε) is an intracellular signaling molecule that mediates chronic pain. This paper addresses the long-term upregulated PKCε in DN associated with endoplasmic reticulum (ER) stress and autophagic formation and correlates to chronic neuropathic pain. We found that thermal hyperalgesia and mechanical allodynia course development were associated with PKCε upregulation after DN but not skin denervation. Pathologically, PKCε upregulation was associated with the expression of inositol-requiring enzyme 1α (IRE1α; ER stress-related molecule) and ubiquitin D (UBD), which are involved in the ubiquitin-proteasome system (UPS)-mediated degradation of misfolded proteins under ER stress. Manders coefficient analyses revealed an approximately 50% colocalized ratio for IRE1α(+):PKCε(+) neurons (0.34-0.48 for M1 and 0.40-0.58 for M2 Manders coefficients). The colocalized coefficients of UBD/PKCε increased (M1: 0.33 ± 0.03 vs. 0.77 ± 0.04, p < 0.001; M2: 0.29 ± 0.05 vs. 0.78 ± 0.04; p < 0.001) in the acute DN stage. In addition, the regulatory subunit p85 of phosphoinositide 3-kinase, which is involved in regulating insulin signaling, exhibited similar expression patterns to those of IRE1α and UBD; for example, it had highly colocalized ratios to PKCε. The ultrastructural examination further confirmed that autophagic formation was associated with PKCε upregulation. Furthermore, PKCεv1-2, a PKCε specific inhibitor, reverses neuropathic pain, ER stress, and autophagic formation in DN. This finding suggests PKCε plays an upstream molecule in DN-associated neuropathic pain and neuropathology and could provide a potential therapeutic target.
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Affiliation(s)
- Yu-Yu Kan
- School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan
| | - Ying-Shuang Chang
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Wen-Chieh Liao
- Doctoral Program in Tissue Engineering and Regenerative Medicine, College of Medicine, National Chung Hsing University, Taichung, 40227, Taiwan
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, 40227, Taiwan
| | - Tzu-Ning Chao
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Yu-Lin Hsieh
- Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- School of Post-Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, 80708, Taiwan.
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Nagaraja S, Tewari SG, Reifman J. Predictive analytics identifies key factors driving hyperalgesic priming of muscle sensory neurons. Front Neurosci 2023; 17:1254154. [PMID: 37942142 PMCID: PMC10629345 DOI: 10.3389/fnins.2023.1254154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Accepted: 09/25/2023] [Indexed: 11/10/2023] Open
Abstract
Hyperalgesic priming, a form of neuroplasticity induced by inflammatory mediators, in peripheral nociceptors enhances the magnitude and duration of action potential (AP) firing to future inflammatory events and can potentially lead to pain chronification. The mechanisms underlying the development of hyperalgesic priming are not well understood, limiting the identification of novel therapeutic strategies to combat chronic pain. In this study, we used a computational model to identify key proteins whose modifications caused priming of muscle nociceptors and made them hyperexcitable to a subsequent inflammatory event. First, we extended a previously validated model of mouse muscle nociceptor sensitization to incorporate Epac-mediated interaction between two G protein-coupled receptor signaling pathways commonly activated by inflammatory mediators. Next, we calibrated and validated the model simulations of the nociceptor's AP response to both innocuous and noxious levels of mechanical force after two subsequent inflammatory events using literature data. Then, by performing global sensitivity analyses that simulated thousands of nociceptor-priming scenarios, we identified five ion channels and two molecular processes (from the 18 modeled transmembrane proteins and 29 intracellular signaling components) as potential regulators of the increase in AP firing in response to mechanical forces. Finally, when we simulated specific neuroplastic modifications in Kv1.1 and Nav1.7 alone as well as with simultaneous modifications in Nav1.7, Nav1.8, TRPA1, and Kv7.2, we observed a considerable increase in the fold change in the number of triggered APs in primed nociceptors. These results suggest that altering the expression of Kv1.1 and Nav1.7 might regulate the neuronal hyperexcitability in primed mechanosensitive muscle nociceptors.
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Affiliation(s)
- Sridevi Nagaraja
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Development Command, Fort Detrick, MD, United States
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Shivendra G. Tewari
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Development Command, Fort Detrick, MD, United States
- The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, United States
| | - Jaques Reifman
- Department of Defense Biotechnology High Performance Computing Software Applications Institute, Telemedicine and Advanced Technology Research Center, US Army Medical Research and Development Command, Fort Detrick, MD, United States
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Sun HJ, Li XY, Wang SS, Shao XM, Du JY, Fang JQ, Fang JF. Intervention mechanism of electroacupuncture on the EP1-TRPV1 pathway in the dorsal root ganglion of rats in the transition from acute to chronic pain. WORLD JOURNAL OF ACUPUNCTURE-MOXIBUSTION 2022. [DOI: 10.1016/j.wjam.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
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Brum ES, Becker G, Fialho MFP, Oliveira SM. Animal models of fibromyalgia: What is the best choice? Pharmacol Ther 2021; 230:107959. [PMID: 34265360 DOI: 10.1016/j.pharmthera.2021.107959] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 07/06/2021] [Accepted: 07/07/2021] [Indexed: 12/11/2022]
Abstract
Fibromyalgia (FM) is a complex syndrome, with an indefinite aetiology and intricate pathophysiology that affects 2 - 3% of the world population. From the beginning of the 2000s, experimental animal models have been developed to mimic clinical FM and help obtain a better understanding of the relevant neurobiology. These animal models have enabled a broad study of FM symptoms and mechanisms, as well as new treatment strategies. Current experimental FM models include the reserpine-induced systemic depletion of biogenic amines, muscle application of acid saline, and stress-based (cold, sound, or swim) approaches, among other emerging models. FM models should: (i) mimic the cardinal symptoms and complaints reported by FM patients (e.g., spontaneous nociception, muscle pain, hypersensitivity); (ii) mimic primary comorbidities that can aggravate quality of life and lead to worse outcomes (e.g., fatigue, sleep disturbance, depression, anxiety); (iii) mimic the prevalent pathological mechanisms (e.g., peripheral and central sensitization, inflammation/neuroinflammation, change in the levels of the excitatory and inhibitory neurotransmitters); and (iv) demonstrate a pharmacological profile similar to the clinical treatment of FM. However, it is difficult for any one of these models to include the entire spectrum of clinical FM features once even FM patients are highly heterogeneous. In the past six years (2015 - 2020), a wide range of experimental FM studies has amounted to the literature reinforcing the need for an updated review. Here we have described, in detail, several approaches used to experimentally study FM, with a focus on recent studies in the field and in previously less discussed mechanisms. We highlight each model's challenges, limitations, and future directions, intending to help preclinical researchers establish the correct experimental FM model to use depending on their goals.
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Affiliation(s)
- Evelyne Silva Brum
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Gabriela Becker
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Maria Fernanda Pessano Fialho
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Sara Marchesan Oliveira
- Graduate Program in Biological Sciences: Biochemistry Toxicology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil; Department of Biochemistry and Molecular Biology, Centre of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil.
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Marked sexual dimorphism in neuroendocrine mechanisms for the exacerbation of paclitaxel-induced painful peripheral neuropathy by stress. Pain 2021; 161:865-874. [PMID: 31917777 DOI: 10.1097/j.pain.0000000000001798] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Chemotherapy-induced neuropathic pain is a serious adverse effect of chemotherapeutic agents. Clinical evidence suggests that stress is a risk factor for development and/or worsening of chemotherapy-induced peripheral neuropathy (CIPN). We evaluated the impact of stress and stress axis mediators on paclitaxel CIPN in male and female rats. Paclitaxel produced mechanical hyperalgesia, over the 4-day course of administration, peaking by day 7, and still present by day 28, with no significant difference between male and female rats. Paclitaxel hyperalgesia was enhanced in male and female rats previously exposed to unpredictable sound stress, but not in rats that were exposed to sound stress after developing paclitaxel CIPN. We evaluated the role of the neuroendocrine stress axes: in adrenalectomized rats, paclitaxel did not produce hyperalgesia. Intrathecal administration of antisense oligodeoxynucleotides (ODN) reduced expression of β2-adrenergic receptors on nociceptors, and paclitaxel-induced hyperalgesia was slightly attenuated in males, but markedly attenuated in females. By contrast, after intrathecal administration of antisense ODN to decrease expression of glucocorticoid receptors, hyperalgesia was markedly attenuated in males, but unaffected in females. Both ODNs together markedly attenuated paclitaxel-induced hyperalgesia in both males and females. We evaluated paclitaxel-induced CIPN in stress-resilient (produced by neonatal handling) and stress-sensitive (produced by neonatal limited bedding). Neonatal handling significantly attenuated paclitaxel-induced CIPN in adult male, but not in adult female rats. Neonatal limited bedding did not affect the magnitude of paclitaxel-induced CIPN in either male or female. This study provides evidence that neuroendocrine stress axis activity has a marked, sexually dimorphic, effect on paclitaxel-induced painful CIPN.
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Garza Carbajal A, Ebersberger A, Thiel A, Ferrari L, Acuna J, Brosig S, Isensee J, Moeller K, Siobal M, Rose-John S, Levine J, Schaible HG, Hucho T. Oncostatin M induces hyperalgesic priming and amplifies signaling of cAMP to ERK by RapGEF2 and PKA. J Neurochem 2020; 157:1821-1837. [PMID: 32885411 DOI: 10.1111/jnc.15172] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 08/19/2020] [Accepted: 08/20/2020] [Indexed: 12/19/2022]
Abstract
Hyperalgesic priming is characterized by enhanced nociceptor sensitization by pronociceptive mediators, prototypically PGE2 . Priming has gained interest as a mechanism underlying the transition to chronic pain. Which stimuli induce priming and what cellular mechanisms are employed remains incompletely understood. In adult male rats, we present the cytokine Oncostatin M (OSM), a member of the IL-6 family, as an inducer of priming by a novel mechanism. We used a high content microscopy based approach to quantify the activation of endogenous PKA-II and ERK of thousands sensory neurons in culture. Incubation with OSM increased and prolonged ERK activation by agents that increase cAMP production such as PGE2 , forskolin, and cAMP analogs. These changes were specific to IB4/CaMKIIα positive neurons, required protein translation, and increased cAMP-to-ERK signaling. In both, control and OSM-treated neurons, cAMP/ERK signaling involved RapGEF2 and PKA but not Epac. Similar enhancement of cAMP-to-ERK signaling could be induced by GDNF, which acts mostly on IB4/CaMKIIα-positive neurons, but not by NGF, which acts mostly on IB4/CaMKIIα-negative neurons. In vitro, OSM pretreatment rendered baseline TTX-R currents ERK-dependent and switched forskolin-increased currents from partial to full ERK-dependence in small/medium sized neurons. In summary, priming induced by OSM uses a novel mechanism to enhance and prolong coupling of cAMP/PKA to ERK1/2 signaling without changing the overall pathway structure.
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Affiliation(s)
- Anibal Garza Carbajal
- Department of Anaesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital Cologne, University Cologne, Cologne, Germany
| | | | - Alina Thiel
- Department of Anaesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital Cologne, University Cologne, Cologne, Germany
| | - Luiz Ferrari
- Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Jeremy Acuna
- Department of Anaesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital Cologne, University Cologne, Cologne, Germany
| | - Stephanie Brosig
- Department of Anaesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital Cologne, University Cologne, Cologne, Germany
| | - Joerg Isensee
- Department of Anaesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital Cologne, University Cologne, Cologne, Germany
| | - Katharina Moeller
- Department of Anaesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital Cologne, University Cologne, Cologne, Germany
| | - Maike Siobal
- Department of Anaesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital Cologne, University Cologne, Cologne, Germany
| | | | - Jon Levine
- Department of Oral and Maxillofacial Surgery, University of California San Francisco, San Francisco, CA, USA
| | | | - Tim Hucho
- Department of Anaesthesiology and Intensive Care Medicine, Translational Pain Research, University Hospital Cologne, University Cologne, Cologne, Germany
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Wang S, Du J, Shao F, Wang W, Sun H, Shao X, Liang Y, Liu B, Fang J, Fang J. Electroacupuncture Regulates Pain Transition by Inhibiting the mGluR5-PKCε Signaling Pathway in the Dorsal Root Ganglia. J Pain Res 2020; 13:1471-1483. [PMID: 32606913 PMCID: PMC7311359 DOI: 10.2147/jpr.s251948] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 05/27/2020] [Indexed: 12/24/2022] Open
Abstract
Background Acute pain can transition to chronic pain, presenting a major clinical challenge. Electroacupuncture (EA) can partly prevent the transition from acute to chronic pain. However, little is known about the mechanisms underlying the effect of EA. This study investigated the effect of EA on pain transition and the activation of metabotropic glutamate receptor 5 (mGluR5)–protein kinase C epsilon (PKCε) signaling pathway in the dorsal root ganglia (DRG). Methods The hyperalgesic priming model was established by the sequential intraplantar injection of carrageenan (1%, 100 μL) and prostaglandin E2 (PGE2) into the left hind paw of rats. EA treatment (2/100 Hz, 30 min, once/day) was applied at bilateral Zusanli (ST36) and Kunlun (BL60) acupoints in rats. Von Frey filaments were used to investigate the mechanical withdrawal threshold (MWT) at different time points. The protein expression levels of mGluR5 and PKCε in the ipsilateral L4-L6 DRGs of rats were detected by Western blot. Some pharmacological experiments were performed to evaluate the relationship between mGluR5, PKCε and the MWT. It was also used to test the effects of EA on the expression levels of mGluR5 and PKCε and changes in the MWT. Results Sequential injection of carrageenan and PGE2 significantly decreased the MWT of rats and up-regulated the expression level of mGluR5 and PKCε in the ipsilateral L4-L6 DRGs. EA can reverse the hyperalgesic priming induced by sequential injection of carrageenan/PGE and down-regulate the protein expression of mGluR5 and PKCε. Glutamate injection instead of PGE2 can mimic the hyperalgesic priming model. Pharmacological blocking of mGluR5 with specific antagonist MTEP can prevent the hyperalgesic priming and inhibit the activation of PKCε in DRGs. Furthermore, EA also produced analgesic effect on the hyperalgesic priming rats induced by carrageenan/mGluR5 injection and inhibited the high expression of PKCε. Sham EA produced none analgesic and regulatory effect. Conclusion EA can regulate pain transition and it may relate with its inhibitory effect on the activation of mGluR5-PKCε signaling pathway in the DRGs.
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Affiliation(s)
- Sisi Wang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
| | - Junying Du
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
| | - Fangbing Shao
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
| | - Wen Wang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
| | - Haiju Sun
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
| | - Xiaomei Shao
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
| | - Yi Liang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
| | - Boyi Liu
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
| | - Jianqiao Fang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
| | - Junfan Fang
- Department of Neurobiology and Acupuncture Research, The Third Clinical Medical College, Zhejiang Chinese Medical University, Key Laboratory of Acupuncture and Neurology of Zhejiang Province, Hangzhou 310053, People's Republic of China
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Role of GPCR (mu-opioid)-receptor tyrosine kinase (epidermal growth factor) crosstalk in opioid-induced hyperalgesic priming (type II). Pain 2019; 159:864-875. [PMID: 29447132 DOI: 10.1097/j.pain.0000000000001155] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Repeated stimulation of mu-opioid receptors (MORs), by an MOR-selective agonist DAMGO induces type II priming, a form of nociceptor neuroplasticity, which has 2 components: opioid-induced hyperalgesia (OIH) and prolongation of prostaglandin-E2 (PGE2)-induced hyperalgesia. We report that intrathecal antisense knockdown of the MOR in nociceptors, prevented the induction of both components of type II priming. Type II priming was also eliminated by SSP-saporin, which destroys the peptidergic class of nociceptors. Because the epidermal growth factor receptor (EGFR) participates in MOR signaling, we tested its role in type II priming. The EGFR inhibitor, tyrphostin AG 1478, prevented the induction of prolonged PGE2-induced hyperalgesia, but not OIH, when tested out to 30 days after DAMGO. However, even when repeatedly injected, an EGFR agonist did not induce hyperalgesia or priming. A phosphopeptide, which blocks the interaction of Src, focal adhesion kinase (FAK), and EGFR, also prevented DAMGO-induced prolongation of PGE2 hyperalgesia, but only partially attenuated the induction of OIH. Inhibitors of Src and mitogen-activated protein kinase (MAPK) also only attenuated OIH. Inhibitors of matrix metalloproteinase, which cleaves EGF from membrane protein, markedly attenuated the expression, but did not prevent the induction, of prolongation of PGE2 hyperalgesia. Thus, although the induction of prolongation of PGE2-induced hyperalgesia at the peripheral terminal of peptidergic nociceptor is dependent on Src, FAK, EGFR, and MAPK signaling, Src, FAK, and MAPK signaling is only partially involved in the induction of OIH.
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Synthetic chalcones as potential tool for acute- and chronic-pain control. Biomed Pharmacother 2018; 104:437-450. [PMID: 29787991 DOI: 10.1016/j.biopha.2018.05.075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Revised: 05/16/2018] [Accepted: 05/16/2018] [Indexed: 12/18/2022] Open
Abstract
The purpose of this study was to validate the potential anti-hypersensitive activity of two chalcones, (2E)-1-(4-aminophenyl)-3-(4-nitrophenyl)prop-2-en-1-one (ANCh) and N-{4-[(2E)-3-(4-nitrophenyl)prop-2-enoil]phenyl}acetamide (AcANCh), by different models of acute and persistent pain in mice, besides in silico analysis. Molecules computational investigation for prediction of Lipinki's and Veber's rules to determine solubility, % absorption, drug likeness and toxicity liabilities was performed. Male and female C57BL/6 mice (20-30 g, n = 6) were used. Firstly, mice were pre-treated with the compounds ANCh or AcANCh and then submitted to the models of acute hypersensitivity by the intraplantar injection of different phlogistic agents. The mechanical sensitivity was assessed using von Frey hairs (0.6 g). The obtained data shows that both compounds presented important inhibitory effects on mechanical hypersensitivity induced by carrageenan (with oral bioavailability). The anti-hypersensitive effect was also accompanied by the interference in leukocyte migration, interleukin-1β (IL-1β) and tumour necrosis factor (TNF) levels reduction and by the absence of unspecific effects. Added to the in vivo results, the in silico analysis presented none violation in Lipinski's or Veber's rules, good probability to cell membrane permeability and oral bioavailability, positive values of drug likeness and few risk of computational toxicity. ANCh partially reduced the hypersensitivity induced by IL-1β and TNF, epinephrine and prostaglandin E2 (PGE2). AcANCh had similar effect, except for the absent of inhibition in PGE2-injected mice. Both compounds were capable of reducing the mechanical hypersensitivity presented in all persistent models of hypersensitivity (inflammatory pain, chronic nerve constriction and cancer pain), with emphasis for ANCh. These results suggest that both chalcones could represent good strategies for the control of acute and chronic pain, without important side effects. ANCh seems to involve cell migration and cytokines production as the main mechanism, together with interference in PGE2 neuronal sensitization pathway. In vivo and in silico analyses reinforce the potential characteristics of the compounds to become future drugs.
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Sung K, Ferrari LF, Yang W, Chung C, Zhao X, Gu Y, Lin S, Zhang K, Cui B, Pearn ML, Maloney MT, Mobley WC, Levine JD, Wu C. Swedish Nerve Growth Factor Mutation (NGF R100W) Defines a Role for TrkA and p75 NTR in Nociception. J Neurosci 2018; 38:3394-3413. [PMID: 29483280 PMCID: PMC5895035 DOI: 10.1523/jneurosci.1686-17.2018] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 01/23/2018] [Accepted: 02/12/2018] [Indexed: 12/14/2022] Open
Abstract
Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGFβ sequence (NGFR100W) in patients with hereditary sensory and autonomic neuropathy type V (HSAN V) made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular, and live-imaging experiments to examine the binding and signaling properties of NGFR100W Our results show that, similar to the wild-type NGF (wtNGF), the naturally occurring NGFR100W mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation. However, NGFR100W failed to bind and stimulate the 75 kDa neurotrophic factor receptor (p75NTR)-mediated signaling cascades (i.e., the RhoA-Cofilin pathway). Intraplantar injection of NGFR100W into adult rats induced neither TrkA-mediated thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia based on agonism for TrkA signaling. Together, our studies provide evidence that NGFR100W retains trophic support capability through TrkA and one aspect of its nociceptive signaling, but fails to engage p75NTR signaling pathways. Our findings suggest that wtNGF acts via TrkA to regulate the delayed priming of nociceptive responses. The integration of both TrkA and p75NTR signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception.SIGNIFICANCE STATEMENT In the present study, we characterized the naturally occurring nerve growth factor NGFR100W mutant that is associated with hereditary sensory and autonomic neuropathy type V. We have demonstrated for the first time that NGFR100W retains trophic support capability through TrkA, but fails to engage p75NTR signaling pathways. Furthermore, after intraplantar injection into adult rats, NGFR100W induced neither thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia. We have also provided evidence that the integration of both TrkA- and p75NTR-mediated signaling appears to regulate neuroplastic effects of NGF in peripheral nociception. Our study with NGFR100W suggests that it is possible to uncouple trophic effect from nociceptive function, both induced by wild-type NGF.
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Affiliation(s)
| | - Luiz F Ferrari
- Department of Oral Surgery, University of California San Francisco, San Francisco, California 94143
| | - Wanlin Yang
- Department of Neurosciences
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 200025
| | - ChiHye Chung
- Department of Biological Sciences, Konkuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul, 143-701, South Korea
| | | | - Yingli Gu
- Department of Neurosciences
- Department of Neurology, the Fourth Hospital of Harbin Medical University, Harbin, Heilongjiang, China 150001
| | - Suzhen Lin
- Department of Neurosciences
- Department of Neurology and Institute of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China 200025
| | - Kai Zhang
- Department of Chemistry
- Department of Biochemistry, Neuroscience Program, Center for Biophysics and Quantitative Biology, Chemistry-Biology Interface Training Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, and
| | | | - Matthew L Pearn
- Department of Anesthesiology, University of California San Diego, School of Medicine, La Jolla, California 92093
- V.A. San Diego Healthcare System, San Diego, California 92161
| | - Michael T Maloney
- Department of Neurosciences, Stanford University, Stanford, California 94305
| | | | - Jon D Levine
- Department of Oral Surgery, University of California San Francisco, San Francisco, California 94143
| | - Chengbiao Wu
- Department of Neurosciences,
- V.A. San Diego Healthcare System, San Diego, California 92161
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Anti-hypersensitivity effects of the phthalimide derivative N-(4methyl-phenyl)-4-methylphthalimide in different pain models in mice. Biomed Pharmacother 2017; 96:503-512. [PMID: 29032334 DOI: 10.1016/j.biopha.2017.10.048] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 09/26/2017] [Accepted: 10/09/2017] [Indexed: 01/20/2023] Open
Abstract
The treatment of chronic pain remains a challenge for clinicians worldwide, independent of its pathogenesis. It motivates several studies attempting to discover strategies to treat the disease. The in silico analysis using molecular docking approach demonstrated that the phthalimide N-(4methyl-phenyl)-4-methylphthalimide (MPMPH-1) presented high affinity to adenylyl-cyclase enzyme (AC). It also prominently reduced the mechanical hypersensitivity of mice challenged by Forskolin, an AC activator. This effect lasted for up to 48h after Forskolin injection, presenting activity longer than MDL-12330A (AC inhibitor). MPMPH-1 was also effective in reducing the hypersensitivity induced by IL-1β, bradykinin, prostaglandin E2 or epinephrine, chemical mediators that have, among others, AC as pivotal protein in their signalling cascade to induce mechanical-pain behaviour. The compound presented marked inhibition in inflammatory-pain models induced by carrageenan, lipopolysaccharide or complete Freund's adjuvant, including neutrophil migration inhibition. Furthermore, it also seems to act in both peripheral and pain central-control pathways, being also effective in reducing the persistent cancer-pain behaviour induced by melanoma cells in mice. MPMPH-1 could represent a promising pharmacological tool to treat acute and chronic painful diseases, with good bioavailability, local activity, and lack of locomotor-activity interference. Further studies are necessary to determine the exact mechanism of action but it seems to involve AC enzyme as possible target.
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Ferrari LF, Araldi D, Green P, Levine JD. Age-Dependent Sexual Dimorphism in Susceptibility to Develop Chronic Pain in the Rat. Neuroscience 2017; 387:170-177. [PMID: 28676241 DOI: 10.1016/j.neuroscience.2017.06.044] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Revised: 05/18/2017] [Accepted: 06/22/2017] [Indexed: 01/08/2023]
Abstract
Neonatal pain has been suggested to contribute to the development and/or persistence of adult pain. Observations from animal models have shown that neonatal inflammation produces long-term changes in sensory neuron function, which can affect the susceptibility of adults to develop persistent pain. We used a preclinical model of transition to chronic pain, hyperalgesic priming, in which a previous inflammatory stimulus triggers a long-lasting increase in responsiveness to pro-algesic mediators, prototypically prostaglandin E2 (PGE2), to investigate if post-natal age influences susceptibility of adult rats to develop chronic pain. Priming was induced by tumor necrosis factor alpha (TNFα), in male and female rats, 1, 2, 3, 4, 5 or 7weeks after birth. When adults (8weeks after birth), to evaluate for the presence of priming, PGE2 was injected at the same site as TNFα. In males that had received TNFα at post-natal weeks 1, 2 or 3, priming was attenuated compared to the 4-, 5- and 7-week-old treated groups, in which robust priming developed. In contrast, in females treated with TNFα at post-natal week 1, 2, 3, or 4, but not at 5 or 7, priming was present. This age and sex difference in the susceptibility to priming was estrogen-dependent, since injection of TNFα in 3-week-old males and 5-week-old females, in the presence of the estrogen receptor antagonist ICI 182,780, did produce priming. These results suggest that estrogen levels, which vary differently in males and females over the post-natal period, until they stabilize after puberty, impact pain as an adult.
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Affiliation(s)
- Luiz F Ferrari
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA.
| | - Dioneia Araldi
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA.
| | - Paul Green
- Departments of Oral & Maxillofacial Surgery, Preventive & Restorative Dental Sciences, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA.
| | - Jon D Levine
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA.
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Spindola HM, Grando R, Figueiredo MC, Basting R, Queiroz NCA, de Fátima Â, de Carvalho JE, Wang ZJ, Foglio MA. Derivatives of furanditerpenes from Pterodon genus: Pharmacological studies disclose their potential as chronic pain relief in mice. Eur J Pharmacol 2017; 804:68-77. [PMID: 28322839 DOI: 10.1016/j.ejphar.2017.03.030] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Revised: 03/15/2017] [Accepted: 03/15/2017] [Indexed: 02/07/2023]
Abstract
Pterodon genus fruits are commercially available at the Brazilian medicinal market used in folk medicine due to their anti-inflammatory, analgesic, and anti-rheumatic effects. Previous studies demonstrated that furanditerpenes possessing vouacapan skeleton, isolated from Pterodon genus, possess expressive antinociceptive activities, with promising moiety for the development of new analgesic products. The antinociceptive properties of compounds 6α,7β-6α-hidroxivouacapan-7β-17β-lactone (HVL) and 6α-oxovouacapan-7β-17β-lactone (OVL), semi-synthetic analogues of furanditerpenes previously reported as analgesic agents were evaluated on animal experimental models (Spindola et al., 2010, 2011). The chemical-induced pain methods used in the present work, demonstrated for the first time that both compounds HVL and OVL have potential as important templates for the development of chronic pain control drugs. The main findings of this work were that both compounds were: effective in the writhing test; reduced paw edema in the carrageenan test; effective in the inflammatory phase of the formalin test corroborating their activity against inflammatory pain conditions; effective on reducing pain through the stimulation of vanilloid receptors sensible to capsaicin (an important pathway for chronic pain maintenance); reduced the pain stimulus caused by PGE2 injection (a pathway involved in chronic pain hypersensitivity); effective on decreasing mechanical allodynia in the CFA-model, demonstrating their potential use against chronic pain disorders.
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Affiliation(s)
- Humberto M Spindola
- CPQBA, University of Campinas, P.O. Box 6171, 13083-970 Campinas, SP, Brazil; UIC, University of Illinois at Chicago, 3320 MBRB, MC 865 Chicago, IL, USA
| | - Rogério Grando
- CPQBA, University of Campinas, P.O. Box 6171, 13083-970 Campinas, SP, Brazil
| | | | - Rosana Basting
- CPQBA, University of Campinas, P.O. Box 6171, 13083-970 Campinas, SP, Brazil
| | - N C A Queiroz
- CPQBA, University of Campinas, P.O. Box 6171, 13083-970 Campinas, SP, Brazil
| | - Ângelo de Fátima
- GEQOB, ICEx, Federal University of Minas Gerais, 31270-901 Belo Horizonte, MG, Brazil
| | - João E de Carvalho
- CPQBA, University of Campinas, P.O. Box 6171, 13083-970 Campinas, SP, Brazil; FCF, University of Campinas, P.O. Box 6029, 13083-859 Campinas, SP, Brazil
| | - Zaijie J Wang
- UIC, University of Illinois at Chicago, 3320 MBRB, MC 865 Chicago, IL, USA
| | - M A Foglio
- CPQBA, University of Campinas, P.O. Box 6171, 13083-970 Campinas, SP, Brazil; FCF, University of Campinas, P.O. Box 6029, 13083-859 Campinas, SP, Brazil.
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Gi-protein-coupled 5-HT1B/D receptor agonist sumatriptan induces type I hyperalgesic priming. Pain 2017; 157:1773-1782. [PMID: 27075428 DOI: 10.1097/j.pain.0000000000000581] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
We have recently described a novel form of hyperalgesic priming (type II) induced by agonists at two clinically important Gi-protein-coupled receptors (Gi-GPCRs), mu-opioid and A1-adenosine. Like mu-opioids, the antimigraine triptans, which act at 5-HT1B/D Gi-GPCRs, have been implicated in pain chronification. We determined whether sumatriptan, a prototypical 5-HT1B/D agonist, produces type II priming. Characteristic of hyperalgesic priming, intradermal injection of sumatriptan (10 ng) induced a change in nociceptor function such that a subsequent injection of prostaglandin-E2 (PGE2) induces prolonged mechanical hyperalgesia. However, onset to priming was delayed 3 days, characteristic of type I priming. Also characteristic of type I priming, a protein kinase Cε, but not a protein kinase A inhibitor attenuated the prolongation phase of PGE2 hyperalgesia. The prolongation of PGE2 hyperalgesia was also permanently reversed by intradermal injection of cordycepin, a protein translation inhibitor. Also, hyperalgesic priming did not occur in animals pretreated with pertussis toxin or isolectin B4-positive nociceptor toxin, IB4-saporin. Finally, as observed for other agonists that induce type I priming, sumatriptan did not induce priming in female rats. The prolongation of PGE2 hyperalgesia induced by sumatriptan was partially prevented by coinjection of antagonists for the 5-HT1B and 5-HT1D, but not 5-HT7, serotonin receptors and completely prevented by coadministration of a combination of the 5-HT1B and 5-HT1D antagonists. Moreover, the injection of selective agonists, for 5-HT1B and 5-HT1D receptors, also induced hyperalgesic priming. Our results suggest that sumatriptan, which signals through Gi-GPCRs, induces type I hyperalgesic priming, unlike agonists at other Gi-GPCRs, which induce type II priming.
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16
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The Role of Adenosine Signaling in Headache: A Review. Brain Sci 2017; 7:brainsci7030030. [PMID: 28335379 PMCID: PMC5366829 DOI: 10.3390/brainsci7030030] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 03/05/2017] [Accepted: 03/07/2017] [Indexed: 12/18/2022] Open
Abstract
Migraine is the third most prevalent disease on the planet, yet our understanding of its mechanisms and pathophysiology is surprisingly incomplete. Recent studies have built upon decades of evidence that adenosine, a purine nucleoside that can act as a neuromodulator, is involved in pain transmission and sensitization. Clinical evidence and rodent studies have suggested that adenosine signaling also plays a critical role in migraine headache. This is further supported by the widespread use of caffeine, an adenosine receptor antagonist, in several headache treatments. In this review, we highlight evidence that supports the involvement of adenosine signaling in different forms of headache, headache triggers, and basic headache physiology. This evidence supports adenosine A2A receptors as a critical adenosine receptor subtype involved in headache pain. Adenosine A2A receptor signaling may contribute to headache via the modulation of intracellular Cyclic adenosine monophosphate (cAMP) production or 5' AMP-activated protein kinase (AMPK) activity in neurons and glia to affect glutamatergic synaptic transmission within the brainstem. This evidence supports the further study of adenosine signaling in headache and potentially illuminates it as a novel therapeutic target for migraine.
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17
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Sexual Dimorphism in a Reciprocal Interaction of Ryanodine and IP 3 Receptors in the Induction of Hyperalgesic Priming. J Neurosci 2017; 37:2032-2044. [PMID: 28115480 DOI: 10.1523/jneurosci.2911-16.2017] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 01/12/2017] [Accepted: 01/13/2017] [Indexed: 12/15/2022] Open
Abstract
Hyperalgesic priming, a model of pain chronification in the rat, is mediated by ryanodine receptor-dependent calcium release. Although ryanodine induces priming in both sexes, females are 5 orders of magnitude more sensitive, by an estrogen receptor α (EsRα)-dependent mechanism. An inositol 1,4,5-triphosphate (IP3) receptor inhibitor prevented the induction of priming by ryanodine. For IP3 induced priming, females were also more sensitive. IP3-induced priming was prevented by pretreatment with inhibitors of the sarcoendoplasmic reticulum calcium ATPase and ryanodine receptor. Antisense to EsRα prevented the induction of priming by low-dose IP3 in females. The induction of priming by an EsRα agonist was ryanodine receptor-dependent and prevented by the IP3 antagonist. Thus, an EsRα-dependent bidirectional interaction between endoplasmic reticulum IP3 and ryanodine receptor-mediated calcium signaling is present in the induction of hyperalgesic priming, in females. In cultured male DRG neurons, IP3 (100 μm) potentiated depolarization-induced transients produced by extracellular application of high-potassium solution (20 mm, K20), in nociceptors incubated with β-estradiol. This potentiation of depolarization-induced calcium transients was blocked by the IP3 antagonist, and not observed in the absence of IP3 IP3 potentiation was also blocked by ryanodine receptor antagonist. The application of ryanodine (2 nm), instead of IP3, also potentiated K20-induced calcium transients in the presence of β-estradiol, in an IP3 receptor-dependent manner. Our results point to an EsRα-dependent, reciprocal interaction between IP3 and ryanodine receptors that contributes to sex differences in hyperalgesic priming.SIGNIFICANCE STATEMENT The present study demonstrates a mechanism that plays a role in the marked sexual dimorphism observed in a model of the transition to chronic pain, hyperalgesic priming. This mechanism involves a reciprocal interaction between the endoplasmic reticulum receptors, IP3 and ryanodine, in the induction of priming, regulated by estrogen receptor α in the nociceptor of female rats. The presence of this signaling pathway modulating the susceptibility of nociceptors to develop plasticity may contribute to our understanding of sex differences observed clinically in chronic pain syndromes.
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Ferrari LF, Araldi D, Levine JD. Regulation of Expression of Hyperalgesic Priming by Estrogen Receptor α in the Rat. THE JOURNAL OF PAIN 2017; 18:574-582. [PMID: 28089711 DOI: 10.1016/j.jpain.2016.12.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 11/03/2016] [Revised: 12/06/2016] [Accepted: 12/21/2016] [Indexed: 01/18/2023]
Abstract
Hyperalgesic priming, a sexually dimorphic model of transition to chronic pain, is expressed as prolongation of prostaglandin E2-induced hyperalgesia by the activation of an additional pathway including an autocrine mechanism at the plasma membrane. The autocrine mechanism involves the transport of cyclic adenosine monophosphate (AMP) to the extracellular space, and its conversion to AMP and adenosine, by ecto-5'phosphodiesterase and ecto-5'nucleotidase, respectively. The end product, adenosine, activates A1 receptors, producing delayed onset prolongation of prostaglandin E2 hyperalgesia. We tested the hypothesis that the previously reported, estrogen-dependent, sexual dimorphism observed in the induction of priming is present in the mechanisms involved in its expression, as a regulatory effect on ecto-5'nucleotidase by estrogen receptor α (EsRα), in female rats. In the primed paw AMP hyperalgesia was dependent on conversion to adenosine, being prevented by ecto-5'nucleotidase inhibitor α,β-methyleneadenosine 5'-diphosphate sodium salt and A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine. To investigate an interaction between EsRα and ecto-5'nucleotidase, we treated primed female rats with oligodeoxynucleotide antisense or mismatch against EsRα messenger RNA. Whereas in rats treated with antisense AMP-induced hyperalgesia was abolished, the A1 receptor agonist N6-cyclopentiladenosine still produced hyperalgesia. Thus, EsRα interacts with this autocrine pathway at the level of ecto-5'nucleotidase. These results demonstrate a sexually dimorphic mechanism for the expression of priming. PERSPECTIVE This study presents evidence of an estrogen-dependent mechanism of expression of chronic pain in female rats, supporting the suggestion that differential targets must be considered when establishing protocols for the treatment of painful conditions in men and women.
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Affiliation(s)
- Luiz F Ferrari
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
| | - Dionéia Araldi
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
| | - Jon D Levine
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California.
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Abstract
We have recently shown that repeated exposure of the peripheral terminal of the primary afferent nociceptor to the mu-opioid receptor (MOR) agonist DAMGO ([D-Ala, N-Me-Phe, Gly-ol]-enkephalin acetate salt) induces a model of transition to chronic pain that we have termed type II hyperalgesic priming. Similar to type I hyperalgesic priming, there is a markedly prolonged response to subsequent administration of proalgesic cytokines, prototypically prostaglandin E2 (PGE2). However, type II hyperalgesic priming differs from type I in being rapidly induced, protein kinase A (PKA), rather than PKCε dependent, not reversed by a protein translation inhibitor, occurring in female as well as in male rats, and isolectin B4-negative neuron dependent. We report that, as with the repeated injection of a MOR agonist, the repeated administration of an agonist at the A1-adenosine receptor, also a Gi-protein coupled receptor, N-cyclopentyladenosine (CPA), also produces priming similar to DAMGO-induced type II hyperalgesic priming. In this study, we demonstrate that priming induced by repeated exposure to this A1-adenosine receptor agonist shares the same mechanisms, as MOR-agonist induced priming. However, the prolongation of PGE2 hyperalgesia induced by repeated administration of CPA depends on G-protein αi subunit activation, differently from DAMGO-induced type II priming, in which it depends on the β/γ subunit. These data implicate a novel form of Gi-protein signaling pathway in the type II hyperalgesic priming induced by repeated administration of an agonist at A1-adenosine receptor to the peripheral terminal of the nociceptor.
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Ferrari LF, Khomula EV, Araldi D, Levine JD. Marked Sexual Dimorphism in the Role of the Ryanodine Receptor in a Model of Pain Chronification in the Rat. Sci Rep 2016; 6:31221. [PMID: 27499186 PMCID: PMC4976309 DOI: 10.1038/srep31221] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 07/14/2016] [Indexed: 12/19/2022] Open
Abstract
Hyperalgesic priming, an estrogen dependent model of the transition to chronic pain, produced by agonists at receptors that activate protein kinase C epsilon (PKCε), occurs in male but not in female rats. However, activation of second messengers downstream of PKCε, such as the ryanodine receptor, induces priming in both sexes. Since estrogen regulates intracellular calcium, we investigated the interaction between estrogen and ryanodine in the susceptibility to develop priming in females. The lowest dose of ryanodine able to induce priming in females (1 pg) is 1/100,000th that needed in males (100 ng), an effect dependent on the activation of ryanodine receptors. Treatment of female rats with antisense to estrogen receptor alpha (ERα), but not beta (ERβ), mRNA, prevented the induction of priming by low dose ryanodine, and the ERα agonist, PPT, induced ryanodine receptor-dependent priming. In vitro application of ryanodine in low concentration (2 nM) to small DRG neurons cultured from females, significantly potentiated calcium release via ryanodine receptors induced by caffeine. This effect was only observed in IB4+ neurons, cultured in the presence of β-estradiol or PPT. Our results demonstrate a profound regulatory role of ERα in ryanodine receptor-dependent transition to chronic pain.
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Affiliation(s)
- Luiz F Ferrari
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Eugen V Khomula
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Dionéia Araldi
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA
| | - Jon D Levine
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, CA 94143, USA
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A-kinase anchoring protein 79/150 coordinates metabotropic glutamate receptor sensitization of peripheral sensory neurons. Pain 2016; 156:2364-2372. [PMID: 26172554 DOI: 10.1097/j.pain.0000000000000295] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Glutamate serves as the primary excitatory neurotransmitter in the nervous system. Previous studies have identified a role for glutamate and group I metabotropic receptors as targets for study in peripheral inflammatory pain. However, the coordination of signaling events that transpire from receptor activation to afferent neuronal sensitization has not been explored. Herein, we identify that scaffolding protein A-kinase anchoring protein 79/150 (AKAP150) coordinates increased peripheral thermal sensitivity after group I metabotropic receptor (mGluR5) activation. In both acute and persistent models of thermal somatosensory behavior, we report that mGluR5 sensitization requires AKAP150 expression. Furthermore, electrophysiological approaches designed to record afferent neuronal activity reveal that mGluR5 sensitization also requires functional AKAP150 expression. In dissociated primary afferent neurons, mGluR5 activation increases TRPV1 responses in an AKAP-dependent manner through a mechanism that induces AKAP association with TRPV1. Experimental results presented herein identify a mechanism of receptor-driven scaffolding association with ion channel targets. Importantly, this mechanism could prove significant in the search for therapeutic targets that repress episodes of acute pain from becoming chronic in nature.
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Meira NA, Rocha LW, da Silva GF, Quintal ZM, Delle Monache F, Cechinel Filho V, Quintão NLM. Chrysophyllum cainito leaves are effective against pre-clinical chronic pain models: Analysis of crude extract, fraction and isolated compounds in mice. JOURNAL OF ETHNOPHARMACOLOGY 2016; 184:30-41. [PMID: 26945982 DOI: 10.1016/j.jep.2016.02.046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2015] [Revised: 02/12/2016] [Accepted: 02/28/2016] [Indexed: 06/05/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Chrysophyllum cainito L. (Sapotaceae), commonly known as caimito or star apple, is a neotropical tree valued for its ornamental quality and edible fruits. Besides its culinary use, the leaves are also popularly used to treat diabetes mellitus and several inflammatory diseases. AIM OF THIS STUDY This study aimed to complement previous data obtained about the anti-hypersensitivity effects of the crude methanol extract (CME), CHCl3 fraction and isolated compounds obtained from C. cainito. MATERIALS AND METHODS The CME, CHCl3 fraction and two isolated triterpenes identified as 3β-Lup-20(29)-en-3-yl acetate (1) and Lup-20(29)-en-3β-O-hexanoate (2) were evaluated regarding their effects using clinical pain models, such as post-operative, inflammatory and neuropathic pain. Acute inflammatory pain models induced by PGE2, epinephrine, LPS and CFA were also used to improve the knowledge about the mechanism of action. RESULTS The animals treated with the CME and submitted to PGE2, epinephrine, LPS or CFA had the mechanical hypersensitivity significantly reduced. When repeatedly administered, the CME enhanced the mechanical withdrawal threshold of mice submitted to post-operative pain model, CFA-induced chronic inflammatory pain and two different models of neuropathic pain. In turn, the CHCl3 fraction presented anti-hypersensitivity effect against epinephrine- or LPS-induced hypersensitivity, with a more prominent activity in both the neuropathic pain models. The compound 1 seems to present the same profile of the CHCl3, whereas compound 2 exhibited activity similar to the CME. CONCLUSIONS This data suggests that the CME effect involves interference in the production, release or action of some chemical mediators, such as PGE2, sympathetic amines, cytokines, etc. Part of these effects was observed with the CHCl3 fraction, emphasizing the prominent inhibition of neuropathic pain. The results also demonstrated that part of the CME effects are due to the presence of the triterpenes 1 and 2, but it is important to mention that we cannot discard the effects of countless other compounds presented in the crude extract, acting in a synergic way.
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Affiliation(s)
| | - Lilian W Rocha
- Programa de Pós-Graduação em Ciências Farmacêuticas, Brazil
| | | | - Zhelmy Martin Quintal
- Facultad de Química, Universidad Autónoma de Yucatán (UADY), Mérida, Yucatán, Mexico
| | - Franco Delle Monache
- Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), CCS, Universidade do Vale do Itajaí (UNIVALI), Santa Catarina, Brazil
| | - Valdir Cechinel Filho
- Programa de Pós-Graduação em Ciências Farmacêuticas, Brazil; Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), CCS, Universidade do Vale do Itajaí (UNIVALI), Santa Catarina, Brazil
| | - Nara Lins Meira Quintão
- Programa de Pós-Graduação em Ciências Farmacêuticas, Brazil; Núcleo de Investigações Químico-Farmacêuticas (NIQFAR), CCS, Universidade do Vale do Itajaí (UNIVALI), Santa Catarina, Brazil.
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Repeated Mu-Opioid Exposure Induces a Novel Form of the Hyperalgesic Priming Model for Transition to Chronic Pain. J Neurosci 2015; 35:12502-17. [PMID: 26354917 DOI: 10.1523/jneurosci.1673-15.2015] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
The primary afferent nociceptor was used as a model system to study mechanisms of pain induced by chronic opioid administration. Repeated intradermal injection of the selective mu-opioid receptor (MOR) agonist DAMGO induced mechanical hyperalgesia and marked prolongation of prostaglandin E2 (PGE2) hyperalgesia, a key feature of hyperalgesic priming. However, in contrast to prior studies of priming induced by receptor-mediated (i.e., TNFα, NGF, or IL-6 receptor) or direct activation of protein kinase Cε (PKCε), the pronociceptive effects of PGE2 in DAMGO-treated rats demonstrated the following: (1) rapid induction (4 h compared with 3 d); (2) protein kinase A (PKA), rather than PKCε, dependence; (3) prolongation of hyperalgesia induced by an activator of PKA, 8-bromo cAMP; (4) failure to be reversed by a protein translation inhibitor; (5) priming in females as well as in males; and (6) lack of dependence on the isolectin B4-positive nociceptor. These studies demonstrate a novel form of hyperalgesic priming induced by repeated administration of an agonist at the Gi-protein-coupled MOR to the peripheral terminal of the nociceptor. Significance statement: The current study demonstrates the molecular mechanisms involved in the sensitization of nociceptors produced by repeated activation of mu-opioid receptors and contributes to our understanding of the painful condition observed in patients submitted to chronic use of opioids.
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Distinct terminal and cell body mechanisms in the nociceptor mediate hyperalgesic priming. J Neurosci 2015; 35:6107-16. [PMID: 25878283 DOI: 10.1523/jneurosci.5085-14.2015] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Hyperalgesic priming, a form of neuroplasticity in nociceptors, is a model of the transition from acute to chronic pain in the rat, which involves signaling from the site of an acute tissue insult in the vicinity of the peripheral terminal of a nociceptor to its cell body that, in turn, induces a signal that travels back to the terminal to mediate a marked prolongation of prostaglandin E2-induced hyperalgesia. In the present experiments, we studied the underlying mechanisms in the cell body and compared them to the mechanisms in the nerve terminal. Injection of a cell-permeant cAMP analog, 8-bromo cAMP, into the dorsal root ganglion induced mechanical hyperalgesia and priming with an onset more rapid than when induced at the peripheral terminal. Priming induced by intraganglion 8-bromo cAMP was prevented by an oligodeoxynucleotide antisense to mRNA for a transcription factor, cAMP response element-binding protein (CREB), and by an inhibitor of importin, which is required for activated CREB to get into the nucleus. While peripheral administration of 8-bromo cAMP also produced hyperalgesia, it did not produce priming. Conversely, interventions administered in the vicinity of the peripheral terminal of the nociceptor that induces priming-PKCε activator, NGF, and TNF-α-when injected into the ganglion produce hyperalgesia but not priming. The protein translation inhibitor cordycepin, injected at the peripheral terminal but not into the ganglion, reverses priming induced at either the ganglion or peripheral terminal of the nociceptor. These data implicate different mechanisms in the soma and terminal in the transition to chronic pain.
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Accounting for the delay in the transition from acute to chronic pain: axonal and nuclear mechanisms. J Neurosci 2015; 35:495-507. [PMID: 25589745 DOI: 10.1523/jneurosci.5147-13.2015] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Acute insults produce hyperalgesic priming, a neuroplastic change in nociceptors that markedly prolongs inflammatory mediator-induced hyperalgesia. After an acute initiating insult, there is a 72 h delay to the onset of priming, for which the underlying mechanism is unknown. We hypothesized that the delay is due to the time required for a signal to travel from the peripheral terminal to the cell body followed by a return signal to the peripheral terminal. We report that when an inducer of hyperalgesic priming (monocyte chemotactic protein 1) is administered at the spinal cord of Sprague Dawley rats, priming is detected at the peripheral terminal with a delay significantly shorter than when applied peripherally. Spinally induced priming is detected not only when prostaglandin E2 (PGE2) is presented to the peripheral nociceptor terminals, but also when it is presented intrathecally to the central terminals in the spinal cord. Furthermore, when an inducer of priming is administered in the paw, priming can be detected in spinal cord (as prolonged hyperalgesia induced by intrathecal PGE2), but only when the mechanical stimulus is presented to the paw on the side where the priming inducer was administered. Both spinally and peripherally induced priming is prevented by intrathecal oligodeoxynucleotide antisense to the nuclear transcription factor CREB mRNA. Finally, the inhibitor of protein translation reversed hyperalgesic priming only when injected at the site where PGE2 was administered, suggesting that the signal transmitted from the cell body to the peripheral terminal is not a newly translated protein, but possibly a newly expressed mRNA.
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Abstract
Animal models of disease states are valuable tools for developing new treatments and investigating underlying mechanisms. They should mimic the symptoms and pathology of the disease and importantly be predictive of effective treatments. Fibromyalgia is characterized by chronic widespread pain with associated co-morbid symptoms that include fatigue, depression, anxiety and sleep dysfunction. In this review, we present different animal models that mimic the signs and symptoms of fibromyalgia. These models are induced by a wide variety of methods that include repeated muscle insults, depletion of biogenic amines, and stress. All potential models produce widespread and long-lasting hyperalgesia without overt peripheral tissue damage and thus mimic the clinical presentation of fibromyalgia. We describe the methods for induction of the model, pathophysiological mechanisms for each model, and treatment profiles.
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Ferrari LF, Levine JD. Plasma membrane mechanisms in a preclinical rat model of chronic pain. THE JOURNAL OF PAIN 2014; 16:60-6. [PMID: 25451625 DOI: 10.1016/j.jpain.2014.10.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Subscribe] [Scholar Register] [Received: 07/14/2014] [Revised: 10/08/2014] [Accepted: 10/21/2014] [Indexed: 01/08/2023]
Abstract
UNLABELLED We have recently shown that the prolongation of prostaglandin E2 hyperalgesia in a preclinical model of chronic pain-hyperalgesic priming-is mediated by release of cyclic adenosine monophosphate from isolectin B4-positive nociceptors and its metabolism by ectonucleotidases to produce adenosine. The adenosine, in turn, acts in an autocrine mechanism at an A1 adenosine receptor whose downstream signaling mechanisms in the nociceptor are altered to produce nociceptor sensitization. We previously showed that antisense against an extracellular matrix molecule, versican, which defines the population of nociceptors involved in hyperalgesic priming, eliminated the prolongation of prostaglandin E2 hyperalgesia. To further evaluate the mechanisms at the interface between the extracellular matrix and the nociceptor's plasma membrane involved in hyperalgesia prolongation, we interrupted a plasma membrane molecule involved in versican signaling, integrin β1, with an antisense oligodeoxynucleotide. Integrin β1 antisense eliminated mechanical hyperalgesia induced by an adenosine A1 receptor agonist, cyclopentyladenosine, in the primed rat. We also disrupted a molecular complex of signaling molecules that contains integrin β1, lipid rafts, with methyl-β-cyclodextrin, which attenuated the prolongation without affecting the acute phase of prostaglandin E2 hyperalgesia, while having no effect on cyclopentyladenosine hyperalgesia. Our findings help to define the plasma membrane mechanisms involved in a preclinical model of chronic pain. PERSPECTIVE The present study contributes to a further understanding of mechanisms involved in the organization of messengers at the plasma membrane that participate in the transition from acute to chronic pain.
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Affiliation(s)
- Luiz F Ferrari
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California
| | - Jon D Levine
- Departments of Medicine and Oral Surgery, and Division of Neuroscience, University of California at San Francisco, San Francisco, California.
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Su YS, Sun WH, Chen CC. Molecular mechanism of inflammatory pain. World J Anesthesiol 2014; 3:71-81. [DOI: 10.5313/wja.v3.i1.71] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2013] [Revised: 09/20/2013] [Accepted: 11/03/2013] [Indexed: 02/07/2023] Open
Abstract
Chronic inflammatory pain resulting from arthritis, nerve injury and tumor growth is a serious public health issue. One of the major challenges in chronic inflammatory pain research is to develop new pharmacologic treatments with long-term efficacy and few side effects. The mediators released from inflamed sites induce complex changes in peripheral and central processing by directly acting on transducer receptors located on primary sensory neurons to transmit pain signals or indirectly modulating pain signals by activating receptors coupled with G-proteins and second messengers. High local proton concentration (acidosis) is thought to be a decisive factor in inflammatory pain and other mediators such as prostaglandin, bradykinin, and serotonin enhance proton-induced pain. Proton-sensing ion channels [transient receptor potential V1 (TRPV1) and the acid-sensing ion channel (ASIC) family] are major receptors for direct excitation of nociceptive sensory neurons in response to acidosis or inflammation. G-protein-coupled receptors activated by prostaglandin, bradykinin, serotonin, and proton modulate functions of TRPV1, ASICs or other ion channels, thus leading to inflammation- or acidosis-linked hyperalgesia. Although detailed mechanisms remain unsolved, clearly different types of pain or hyperalgesia could be due to complex interactions between a distinct subset of inflammatory mediator receptors expressed in a subset of nociceptors. This review describes new directions for the development of novel therapeutic treatments in pain.
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Ferrari LF, Bogen O, Levine JD. Second messengers mediating the expression of neuroplasticity in a model of chronic pain in the rat. THE JOURNAL OF PAIN 2014; 15:312-20. [PMID: 24407022 DOI: 10.1016/j.jpain.2013.12.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/22/2013] [Revised: 12/30/2013] [Accepted: 12/31/2013] [Indexed: 12/28/2022]
Abstract
UNLABELLED Hyperalgesic priming is a model of the transition from acute to chronic pain, in which previous activation of cell surface receptors or direct activation of protein kinase C epsilon markedly prolongs mechanical hyperalgesia induced by pronociceptive cytokines. We recently demonstrated a role of peripheral protein translation, alpha-calmodulin-dependent protein kinase II (αCaMKII) activation, and the ryanodine receptor in the induction of hyperalgesic priming. In the present study, we tested if they also mediate the prolonged phase of prostaglandin E2-induced hyperalgesia. We found that inhibition of αCaMKII and local protein translation eliminates the prolonged phase of prostaglandin E2 hyperalgesia. Although priming induced by receptor agonists or direct activation of protein kinase C epsilon occurs in male but not female rats, activation of αCaMKII and the ryanodine receptor also produces priming in females. As in males, the prolonged phase of prostaglandin E2-induced hyperalgesia in female rats is also protein kinase C epsilon-, αCaMKII-, and protein translation-dependent. In addition, in both male and female primed rats, the prolonged prostaglandin E2-induced hyperalgesia was significantly attenuated by inhibition of MEK/ERK. On the basis of these data, we suggest that the mechanisms previously shown to be involved in the induction of the neuroplastic state of hyperalgesic priming also mediate the prolongation of hyperalgesia. PERSPECTIVES The data provided by this study suggest that direct intervention on specific targets may help to alleviate the expression of chronic hyperalgesic conditions.
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Affiliation(s)
- Luiz F Ferrari
- Division of Neuroscience, Departments of Medicine and Oral Surgery, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, California
| | - Oliver Bogen
- Division of Neuroscience, Departments of Medicine and Oral Surgery, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, California
| | - Jon D Levine
- Division of Neuroscience, Departments of Medicine and Oral Surgery, University of California at San Francisco, 521 Parnassus Avenue, San Francisco, California..
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Role of nociceptor αCaMKII in transition from acute to chronic pain (hyperalgesic priming) in male and female rats. J Neurosci 2013; 33:11002-11. [PMID: 23825405 DOI: 10.1523/jneurosci.1785-13.2013] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
We have previously shown that activation of protein kinase Cε (PKCε) in male rats induces a chronic, long-lasting change in nociceptors such that a subsequent exposure to proinflammatory mediators produces markedly prolonged mechanical hyperalgesia. This neuroplastic change, hyperalgesic priming, is dependent on activation of cytoplasmic polyadenylation element-binding protein (CPEB), downstream of PKCε, and consequent translation of mRNAs in the peripheral terminal of the nociceptor. Since α calmodulin-dependent protein kinase II (αCaMKII), a molecule implicated in neuroplasticity, is a target of CPEB and can also affect CPEB function, we investigated its role in the transition from acute to chronic pain. Priming induced by direct activation of PKCε can be prevented by inhibition of αCaMKII. In addition, direct activation of αCaMKII induces priming, which was not prevented by pretreatment with PKCε antisense, suggesting that αCaMKII is downstream of PKCε in the induction of priming. Activation of ryanodine receptors (RyRs), which can lead to activation of αCaMKII, also induced priming, in a calcium- and αCaMKII-dependent manner. Similarly, inhibition of the RyR and a calcium buffer prevented induction of priming by PKCε. Unlike activation of PKCε, ryanodine and αCaMKII induced priming in female as well as male rats. Our results demonstrate a contribution of αCaMKII to induction of hyperalgesic priming, a phenomenon implicated in the transition from acute to chronic pain.
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Melemedjian OK, Tillu DV, Asiedu MN, Mandell EK, Moy JK, Blute VM, Taylor CJ, Ghosh S, Price TJ. BDNF regulates atypical PKC at spinal synapses to initiate and maintain a centralized chronic pain state. Mol Pain 2013; 9:12. [PMID: 23510079 PMCID: PMC3608966 DOI: 10.1186/1744-8069-9-12] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 03/18/2013] [Indexed: 12/24/2022] Open
Abstract
Background Chronic pain is an important medical problem affecting hundreds of millions of people worldwide. Mechanisms underlying the maintenance of chronic pain states are poorly understood but the elucidation of such mechanisms have the potential to reveal novel therapeutics capable of reversing a chronic pain state. We have recently shown that the maintenance of a chronic pain state is dependent on an atypical PKC, PKMζ, but the mechanisms involved in controlling PKMζ in chronic pain are completely unknown. Here we have tested the hypothesis that brain derived neurotrophic factor (BDNF) regulates PKMζ, and possibly other aPKCs, to maintain a centralized chronic pain state. Results We first demonstrate that although other kinases play a role in the initiation of persistent nociceptive sensitization, they are not involved in the maintenance of this chronic pain state indicating that a ZIP-reversible process is responsible for the maintenance of persistent sensitization. We further show that BDNF plays a critical role in initiating and maintaining persistent nociceptive sensitization and that this occurs via a ZIP-reversible process. Moreover, at spinal synapses, BDNF controls PKMζ and PKCλ nascent synthesis via mTORC1 and BDNF enhances PKMζ phosphorylaton. Finally, we show that BDNF signaling to PKMζ and PKCλ is conserved across CNS synapses demonstrating molecular links between pain and memory mechanisms. Conclusions Hence, BDNF is a key regulator of aPKC synthesis and phosphorylation and an essential mediator of the maintenance of a centralized chronic pain state. These findings point to BDNF regulation of aPKC as a potential therapeutic target for the permanent reversal of a chronic pain state.
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Affiliation(s)
- Ohannes K Melemedjian
- Department of Pharmacology, The University of Arizona School of Medicine, Tucson, AZ, USA
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