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Transient receptor potential (TRP) channels are a family of functionally diverse and widely expressed cation channels involved in a variety of cell signaling and sensory pathways. Research in the last two decades has not only shed light on the physiological roles of the 28 mammalian TRP channels, but also revealed the involvement of specific TRP channels in a plethora of inherited and acquired human diseases. Considering the historical successes of other types of ion channels as therapeutic drug targets, small molecules that target specific TRP channels hold promise as treatments for a variety of human conditions. In recent research, important new findings have highlighted the central role of TRP channels in chronic pain, lower urinary tract disorders, and type 2 diabetes, conditions with an unmet medical need. Here, we discuss how these advances support the development of TRP-channel-based pharmacotherapies as valuable alternatives to the current mainstays of treatment.
Learn More >Much of the opioid epidemic arose from abuse of prescription opioid drugs. This study sought to determine if the combination of a cannabinoid with an opioid could produce additive or synergistic effects on pain, allowing reduction in the opioid dose needed for maximal analgesia.
Learn More >Preemptive analgesia encompasses different perioperative interventions that have the final aim of decreasing postoperative pain and improving recovery. Recently, peripheral analgesic effects of oxytocinergic modulation have been suggested. In this regard, we tested the potential analgesic effects of subcutaneous oxytocin (OT) infiltration in patients submitted to laparoscopic cholecystectomy.
Learn More >Neuropathic pain is frequently driven by ectopic impulse discharge (ectopia) generated in injured peripheral afferent neurons. Observations in the spinal nerve ligation (SNL) model in rats suggest that cell bodies in the dorsal root ganglion (DRG) contribute three times more to the ectopic barrage than the site of nerve injury (neuroma). The DRG is therefore a prime interventional target for pain control. Since DRG ectopia is selectively suppressed with lidocaine at concentrations too low to block axonal impulse propagation, we asked whether targeted delivery of dilute lidocaine to the L5 DRG can relieve L5 SNL-induced tactile allodynia without blocking normal sensation or motor function. Results showed that intraforaminal injection of 10 µL bolus doses of 0.2% lidocaine suppressed allodynia transiently, while sustained infusion over 2 weeks using osmotic minipumps suppressed it for nearly 2 weeks. Bolus injections of morphine or fentanyl were ineffective. Lidocaine applied to the cut spinal nerve end or the L4 DRG did not affect allodynia suggesting that discharge originating in the neuroma and in neighboring "uninjured" afferents makes at best a minor contribution. Spike electrogenesis in the DRG is apparently the primary driver of tactile allodynia in the SNL model of neuropathic pain and it can be controlled selectively by superfusing the relevant DRG(s) with non-blocking concentrations of lidocaine. This approach has potential clinical application in conditions such as postherpetic neuralgia and phantom limb pain in which one or only a few identifiable ganglia are implicated as pain drivers.
Learn More >Migraine is a debilitating condition, however, the pharmacological effects on central nervous system networks following successful therapy is poorly understood. Defining this neurocircuitry is critical to our understanding of the disorder and for the development of anti-migraine drugs. Using an established inflammatory soup (IS) model of migraine-like pathophysiology (N=12) compared to sham synthetic interstitial fluid (SIF) migraine induction (N=12), our aim was to evaluate changes in network-level functional connectivity following sumatriptan-naproxen infusion in awake, conscious, rodents (Sprague-Dawley rats). Sumatriptan-naproxen infusion fMRI data was analyzed using an independent competent analysis approach. Whole brain analysis yielded significant between-group (IS vs. SIF) alterations in functional connectivity across the cerebellar, default mode, basal ganglia, autonomic, and salience networks. These results demonstrate the large-scale anti-migraine effects of sumatriptan-naproxen co-administration following dural sensitization.
Learn More >Experimental and clinical studies suggest that the low-affinity N-methyl-d-aspartate (NMDA) receptor open-channel blockers Mg and memantine are effective in reducing trigeminal nociceptive activation. The aim of the present study was to investigate the apparent effectiveness of these channel blockers using a model of trigeminal activation in vivo. Rats were anesthetized before electrically stimulating the dura mater adjacent the middle meningeal artery. Neurons responding to stimulation were recorded extracellularly using electrophysiological methods while l-glutamate or NMDA and Mg , memantine, or sodium controls were applied locally using microiontophoresis. Microiontophoretic application of Mg or memantine into the trigeminocervical complex inhibited mechanically and electrically-stimulated craniovascular afferent, l-glutamate, or NMDA-evoked neuronal activity at the second order trigeminal synapse of craniovascular afferents. By contrast, intravenous administration of MgSO (100 mg/kg) or memantine (10 mg/kg) did not significantly affect electrically-stimulated afferent-evoked activity within the trigeminocervical complex. The Mg and memantine concentrations achieved after systemic administration may not effectively inhibit activation of the trigeminocervical complex, perhaps providing an explanation for the relatively poor efficacy of these NMDA receptor open-channel blockers for headache treatment in clinical studies. Nevertheless, the present results suggest blocking of NMDA-receptor open channels inhibits nociceptive activation of the trigeminocervical complex. Further exploration of such channel blockers as a therapeutic strategy for primary head pain is warranted. This article is protected by copyright. All rights reserved.
Learn More >To review the pharmacology, efficacy, and safety of the calcitonin gene-related peptide (CGRP) inhibitor erenumab for migraine preventive therapy.
Learn More >Chronic neuropathic pain is a burden to millions of patients every day. Patients with neuropathic pain will also experience acute pain throughout their everyday lives adding to their nociceptive burden. Using nociceptive models in mice this study aimed to investigate the relationship between acute visceral pain and chronic neuropathic pain in spontaneous and affective behaviors. Neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve of C57BL/6J male mice and examined in assays of acetic acid (AA)-induced stretching or conditioned place aversion to assess nociceptive and aversive behaviors. Stretching induced by a low concentration (0.32%) of AA given intraperitoneally was significantly increased in CCI and paclitaxel-treated animals compared to control animals. A higher concentration (1.2%) of AA was able to induce stretching equally in both neuropathic and control mice. In the conditioned place aversion test, an AA concentration of 0.32% did not induce place aversion in either sham or CCI animals. However, the 1.2% concentration of AA-induced higher place aversion scores in CCI mice compared to sham mice. No difference in place conditioning was observed between paclitaxel and vehicle-treated mice. Overall, our results show that peripheral nerve injury and paclitaxel treatment induces hypersensitivity to AA-induced nociception and place aversion.
Learn More >P2Y receptors are G-protein-coupled receptors (GPCRs) for extracellular nucleotides. There are eight mammalian P2Y receptor subtypes divided into two subgroups (P2Y, P2Y, P2Y, P2Y, and P2Y) and (P2Y, P2Y, and P2Y). The P2Y receptors are expressed in various cell types and play important roles in physiology and pathophysiology including inflammatory responses and neuropathic pain. The antagonism of P2Y receptors is used in pharmacotherapy for the prevention and therapy of cardiovascular events. The nucleoside analogue ticagrelor and active metabolites of the thienopyridine compounds ticlopidine, clopidogrel and prasugrel inhibit platelet P2Y receptors and reduce thereby platelet aggregation. The P2Y receptor agonist diquafosol is used for the treatment of the dry eye syndrome. The P2Y receptor subtypes differ in their amino acid sequences, their pharmacological profiles and their signaling transduction pathways. Recently, selective receptor ligands have been developed for all subtypes. The published crystal structures of the human P2Y and P2Y receptors as well as receptor models will facilitate the development of novel drugs for pharmacotherapy.
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