• Chronic pain
• Diclofenac
• Gulf war illness
• K(v)7
• Retigabine

• Epilepsy
• Flupirtine
• KCNQ2
• KCNQ3
• KCNQ5
• Pain
• Retigabine
• SCR2682

The aim of this systematic review is to guide the physician in defining the pharmacologic and rehabilitative therapeutic approaches for adopting the best strategies described in the current literature. The search was conducted in PubMed, EMBASE, Cochrane Library and Web of Science to identify the treatment of small fiber neuropathies. Two reviewers independently reviewed and came to a consensus on which articles met inclusion/exclusion criteria. The authors excluded the duplicates, animal studies and included the English articles in which the treatment of patients with small fiber neuropathies was described. The search identified a total of 975 articles with the keywords “small fiber neuropathy” AND “rehabilitation” OR “therapy” OR “treatment”. Seventy-eight selected full-text were analyzed by the reviewers. Forty-two publications met the inclusion criteria and were included in the systematic review to describe the rehabilitative and pharmacologic treatment of small fiber neuropathies. Despite the range of different protocols of treatment for small fiber neuropathy, other robust trials are needed. In addition, always different therapeutic approaches are used; a unique protocol could be important for the clinicians. More research is needed to build evidence for the best strategy and to delineate a definitive therapeutic protocol.

• small fiber neuropathy
• systematic reviews
• treatment

• diagnosis
• small fiber neuropathy
• systematic reviews

Flupirtine is the first representative in a class of triaminopyridines that exhibits pharmacological properties leading to the suppression of over-excitability of neuronal and non-neuronal cells. Consequently, this drug has been used as a centrally acting analgesic in patients with a range of acute and persistent pain conditions without the adverse effects characteristic of opioids and non-steroidal anti-inflammatory drug and is well tolerated. The pharmacological profile exhibited involves actions on several cellular targets, including Kv7 channels, G-protein-regulated inwardly rectifying K channels and γ-aminobutyric acid type A receptors, but also there is evidence of additional as yet unidentified mechanisms of action involved in the effects of flupirtine. Flupirtine has exhibited effects in a range of cells and tissues related to the locations of these targets. In additional to analgesia, flupirtine has demonstrated pharmacological properties consistent with use as an anticonvulsant, a neuroprotectant, skeletal and smooth muscle relaxant, in treatment of auditory and visual disorders, and treatment of memory and cognitive impairment. Flupirtine is providing important information and clues regarding novel mechanistic approaches to the treatment of a range of clinical conditions involving hyper-excitability of cells. Identification of molecules exhibiting specificity for the pharmacological targets (e.g., Kv7 isoforms) involved in the actions of flupirtine will provide further insight into clinical applications. Whether the broad-spectrum pharmacology of flupirtine or target-specific actions is preferential to gain benefit, especially in complex clinical conditions, requires further investigation. This review will consider recent advancement in understanding of the pharmacological profile and related clinical applications of flupirtine.

• Flupirtine
• Kv7 channels
• GABA_A receptors
• Analgesia
• Seizures
• Neuroprotection
• Myotonia
• Memory
• Tinnitus

• Chronic Pain
• Gulf War Illness
• Muscarinic
• Na(v)1.9
• Pyridostigmine
• TRPA1

• Anatomy and physiology
• Drug therapies
• Inflammatory factors
• Mechanisms of pain
• Neuropathic pain

miR-17-92 is a microRNA cluster with six distinct members. Here, we show that the miR-17-92 cluster and its individual members modulate chronic neuropathic pain. All cluster members are persistently upregulated in primary sensory neurons after nerve injury. Overexpression of miR-18a, miR-19a, miR-19b and miR-92a cluster members elicits mechanical allodynia in rats, while their blockade alleviates mechanical allodynia in a rat model of neuropathic pain. Plausible targets for the miR-17-92 cluster include genes encoding numerous voltage-gated potassium channels and their modulatory subunits. Single-cell analysis reveals extensive co-expression of miR-17-92 cluster and its predicted targets in primary sensory neurons. miR-17-92 downregulates the expression of potassium channels, and reduced outward potassium currents, in particular A-type currents. Combined application of potassium channel modulators synergistically alleviates mechanical allodynia induced by nerve injury or miR-17-92 overexpression. miR-17-92 cluster appears to cooperatively regulate the function of multiple voltage-gated potassium channel subunits, perpetuating mechanical allodynia.

Dysregulation of voltage gated potassium channels is a feature of neuropathic pain. Here in a rat model the authors identify the microRNA cluster miR-17-92 as a regulator of voltage gated potassium channels in the dorsal root ganglion neurons.

Flupirtine (Flu), a triaminopyridine derivative, is a centrally acting, non-opiate analgesic agent. In this study, effects of Flu on K⁺ currents were explored in two types of motor neuron-like cells. Cell exposure to Flu decreased the amplitude of delayed rectifier K⁺ current (I_K(DR)) with a concomitant raise in current inactivation in NSC-34 neuronal cells. The dissociation constant for Flu-mediated increase of I_K(DR) inactivation rate was about 9.8 μM. Neither linopirdine (10 μM), NMDA (30 μM), nor gabazine (10 μM) reversed Flu-induced changes in I_K(DR) inactivation. Addition of Flu shifted the inactivation curve of I_K(DR) to a hyperpolarized potential. Cumulative inactivation for I_K(DR) was elevated in the presence of this compound. Flu increased the amplitude of M-type K⁺ current (I_K(M)) and produced a leftward shift in the activation curve of I_K(M). In another neuronal cells (NG108-15), Flu reduced I_K(DR) amplitude and enhanced the inactivation rate of I_K(DR). The results suggest that Flu acts as an open-channel blocker of delayed-rectifier K⁺ channels in motor neurons. Flu-induced block of I_K(DR) is unlinked to binding to NMDA or GABA receptors and the effects of this agent on K⁺ channels are not limited to its action on M-type K⁺ channels.