Descending projections from neurons in the rostral ventromedial medulla (RVM) make synapses within the superficial dorsal horn (SDH) of the spinal cord that are involved in the modulation of nociception, the development of chronic pain and itch, and an important analgesic target for opioids. This projection is primarily inhibitory, but the relative contribution of GABAergic and glycinergic transmission is unknown and there is limited knowledge about the SDH neurons targeted. Additionally, the details of how spinal opioids mediate analgesia remain unclear, and no study has investigated the opioid modulation of this synapse. We address this using ex vivo optogenetic stimulation of RVM fibres in conjunction with whole-cell patch-clamp recordings from the SDH in spinal cord slices. We demonstrate that both GABAergic and glycinergic neurotransmission is employed and show that SDH target neurons have diverse morphological and electrical properties, consistent with both inhibitory and excitatory interneurons. Then, we describe a subtype of SDH neurons that have a glycine-dominant input, indicating that the quality of descending inhibition across cells is not uniform. Finally, we discovered that the kappa-opioid receptor agonist U69593 presynaptically suppressed most RVM-SDH synapses. By contrast, the mu-opioid receptor agonist DAMGO acted both pre- and post-synaptically at a subset of synapses, and the delta-opioid receptor agonist deltorphin II had little effect. These data provide important mechanistic information about a descending control pathway that regulates spinal circuits. This information is necessary to understand how sensory inputs are shaped and develop more reliable and effective alternatives to current opioid analgesics. Abstract figure legend We combined ex vivo optogenetic stimulation of RVM fibres with whole cell electrophysiology of SDH neurons to investigate the final synapse in a key descending pain modulatory pathway. We demonstrate that both glycine and GABA mediate signalling at the RVM-SDH synapse, that the SDH targets of RVM projections have diverse electrical and morphological characteristics, and that presynaptic inhibition is directly and consistently achieved by kappa opioid agonists. Opioid receptors shown are sized relative to the proportion of neurons that responded to its specific agonists (81 and 84percent of DF and non-DF neurons responded to kappa opioid receptor agonists, respectively. Responses that occurred in <255 percentage of neurons are not indicated here). This article is protected by copyright. All rights reserved.

Tension-type headache (TTH) is the most prevalent neurological disorder worldwide and is characterized by recurrent headaches of mild to moderate intensity, bilateral location, pressing or tightening quality, and no aggravation by routine physical activity. Diagnosis is based on headache history and the exclusion of alternative diagnoses, with clinical criteria provided by the International Classification of Headache Disorders, third edition. Although the biological underpinnings remain unresolved, it seems likely that peripheral mechanisms are responsible for the genesis of pain in TTH, whereas central sensitization may be involved in transformation from episodic to chronic TTH. Pharmacological therapy is the mainstay of clinical management and can be divided into acute and preventive treatments. Simple analgesics have evidence-based effectiveness and are widely regarded as first-line medications for the acute treatment of TTH. Preventive treatment should be considered in individuals with frequent episodic and chronic TTH, and if simple analgesics are ineffective, poorly tolerated or contraindicated. Recommended preventive treatments include amitriptyline, venlafaxine and mirtazapine, as well as some selected non-pharmacological therapies. Despite the widespread prevalence and associated disability of TTH, little progress has been made since the early 2000s owing to a lack of attention and resource allocation by scientists, funding bodies and the pharmaceutical industry.

Nociceptive information is transmitted from the periphery to the cerebral cortex mainly by action potential (AP) conduction in nerve fibers and chemical transmission at synapses. Although this nociceptive transmission is largely inhibited at synapses by analgesics and their adjuvants, it is possible that the antinociceptive drugs inhibit nerve AP conduction, contributing to their antinociceptive effects. Many of the drugs are reported to inhibit the nerve conduction of AP and voltage-gated Na⁺ and K⁺ channels involved in its production. Compound action potential (CAP) is a useful measure to know whether drugs act on nerve AP conduction. Clinically-used analgesics and analgesic adjuvants (opioids, non-steroidal anti-inflammatory drugs, ₂-adrenoceptor agonists, antiepileptics, antidepressants and local anesthetics) were found to inhibit fast-conducting CAPs recorded from the frog sciatic nerve by using the air-gap method. Similar actions were produced by antinociceptive plant-derived chemicals. Their inhibitory actions depended on the concentrations and chemical structures of the drugs. This review article will mention the inhibitory actions of the antinociceptive compounds on CAPs in frog and mammalian peripheral (particularly, sciatic) nerves and on voltage-gated Na⁺ and K⁺ channels involved in AP production. Nerve AP conduction inhibition produced by analgesics and analgesic adjuvants is suggested to contribute to at least a part of their antinociceptive effects.

Epidural block approach and drugs are common options for improving the sensory and motor block duration and postoperative pain management.

The study aimed to compare the analgesic effects of dexmedetomidine and morphine as adjuvants to bupivacaine for epidural anesthesia in leg fracture surgery.

This prospective clinical trial was conducted on patients (n = 80, age range: 18 - 60 years) categorized as ASA class I or II. After a clinical examination, the patients were allocated to receive either lumbar epidural bupivacaine + morphine (BM) (12 mL bupivacaine 0.5% + morphine 2 mg) or bupivacaine + dexmedetomidine (BD) (12 mL bupivacaine 0.5% + dexmedetomidine 1 µg/kg). After drug administration, the sensory block level was assessed at 2-min intervals using the Cold Swab method until it reached the T12 level. At the T12 level of sensory block, the surgery began when motor block reached grade 3 of the modified Bromage scale.

The BD group had a significantly shorter time to reach the sensory and motor block than the BM group (P < 0.001). The duration of sensory and motor block was significantly longer in the group BD than in the BM group (P < 0.001). Moreover, the BD group showed lower VAS scores (P < 0.0001) and longer time to first analgesia demand than the BM group.

Combined bupivacaine + dexmedetomidine prolongs the sensory and motor block duration and controls postoperative pain more effectively, indicating that it is an appropriate combination for epidural anesthesia.

Intraoperative evaluation of analgesia remains today often based on heart rate and arterial pressure fluctuations. None of these parameters is specific. Incorrect handling during this process may increase surgical morbi-mortality of the patients and their acute postoperative pain. The aim of this study was to evaluate the impact of intraoperative analgesia controlled by pupillometry on postoperative analgesic consumption and the pain intensity in the first 12h in the hospital room, after major gynecological surgery.

A prospective, cohort study with allocation of groups of sequentially according to programming of operating room was designed. ASA I-III patients scheduled for elective surgery of abdominal hysterectomy by laparotomy or laparoscopy through intravenous general anesthesia were included. Patients were divided into 2 groups: pupillometry group (P-1), in which intraoperative analgesia was guided by pupillometry, and hemodynamic group (H-2) according to values of blood pressure and heart rate. In the hospitalization room the values of visual analogue scale (VAS) were routinely registered with 3 courts for the study: 3, 8 and 12h of the postoperative period. Postoperative analgesia was standardized as follows: NSAIDs was administered if VAS was ≥ 3 or if the patient expressly requested an analgesic. After this, the efficacy of treatment was assessed. If the patient had pain, the next scheduled drug was given up to an VAS<3. Data for total analgesic consumption administered in the hospital room, VAS and adverse effects were collected within 12h postoperatively.

A total of 59 patients, 30 group P-1 and 29 group H-2, were included. Group P-1 experienced less pain than group H-2, with statistical significance in each phase (VAS 3h, VAS 8h and VAS 12h). These data are consistent with the consumption of analgesics for patients. There was a statistically significant reduction (p<0.001) in the group P-1 (1.80 [DE 0.99]; medium 2, 95% confidence interval 1.43-2.17) compared with group H-2 (5.66 [1.58]; medium 6, 95% confidence interval 5.05-6.26).

Monitoring of the intraoperative analgesia by pupillometry was able to reduce the intensity of the acute postoperative pain and analgesic consumption in the first 12h in the hospital room after major gynecological surgery.