Articles: hyperalgesia.
-
Spinal plasticity, a key process mediating neuropathic pain development, requires ubiquitination-dependent protein turnover. Presynaptic active zone proteins have a crucial role in regulating vesicle exocytosis, which is essential for synaptic plasticity. Nevertheless, the mechanism for ubiquitination-regulated turnover of presynaptic active zone proteins in the progression of spinal plasticity-associated neuropathic pain remains unclear. Here, after research involving Sprague Dawley rats, we reported that spinal nerve ligation (SNL), in addition to causing allodynia, enhances the Rab3-interactive molecule-1α (RIM1α), a major active zone protein presumed to regulate neural plasticity, specifically in the synaptic plasma membranes (SPMs) of the ipsilateral dorsal horn. Spinal RIM1α-associated allodynia was mediated by Fbxo3, which abates Fbxl2-dependent RIM1α ubiquitination. Subsequently, following deubiquitination, enhanced RIM1α directly binds to CaV2.2, resulting in increased CaV2.2 expression in the SPMs of the dorsal horn. While exhibiting no effect on Fbxo3/Fbxl2 signaling, the focal knockdown of spinal RIM1α expression reversed the SNL-induced allodynia and increased spontaneous EPSC (sEPSC) frequency by suppressing RIM1α-facilitated CaV2.2 expression in the dorsal horn. Intrathecal applications of BC-1215 (a Fbxo3 activity inhibitor), Fbxl2 mRNA-targeting small-interfering RNA, and ω-conotoxin GVIA (a CaV2.2 blocker) attenuated RIM1α upregulation, enhanced RIM1α expression, and exhibited no effect on RIM1α expression, respectively. These results confirm the prediction that spinal presynaptic Fbxo3-dependent Fbxl2 ubiquitination promotes the subsequent RIM1α/CaV2.2 cascade in SNL-induced neuropathic pain. Our findings identify a role of the presynaptic active zone protein in pain-associated plasticity. That is, RIM1α-facilitated CaV2.2 expression plays a role in the downstream signaling of Fbxo3-dependent Fbxl2 ubiquitination/degradation to promote spinal plasticity underlying the progression of nociceptive hypersensitivity following neuropathic injury. ⋯ Ubiquitination is a well known process required for protein degradation. Studies investigating pain pathology have demonstrated that ubiquitination contributes to chronic pain by regulating the turnover of synaptic proteins. Here, we found that the spinal presynaptic active zone protein Rab3-interactive molecule-1α (RIM1α) participates in neuropathic pain development by binding to and upregulating the expression of CaV2.2. In addition, Fbxo3 modifies this pathway by inhibiting Fbxl2-mediated RIM1α ubiquitination, suggesting that presynaptic protein ubiquitination makes a crucial contribution to the development of neuropathic pain. Research in this area, now in its infancy, could potentially provide a novel therapeutic strategy for pain relief.
-
Review
Progress of clinical practice on the management of burn-associated pain: Lessons from animal models.
Opioid-based analgesics provide the mainstay for attenuating burn pain, but they have a myriad of side effects including respiratory depression, nausea, impaired gastrointestinal motility, sedation, dependence, physiologic tolerance, and opioid-induced hyperalgesia. To test and develop novel analgesics, validated burn-relevant animal models of pain are indispensable. Herein we review such animal models, which are mostly limited to rodent models of burn-induced, inflammatory, and neuropathic pain. ⋯ Moreover, common clinical concerns such as systemic inflammatory response syndrome and multiple organ dysfunction remain unaddressed. For development of analgesics, these aberrations can significantly alter the potential efficacy and/or adverse effects of a prescribed analgesic following burn trauma. We therefore suggest that a multi-model strategy would be the most clinically relevant when evaluating novel analgesics for use in burn patients.
-
Expert Opin Pharmacother · Sep 2016
Randomized Controlled Trial Comparative StudyEvaluation of the antihyperalgesic effect of tapentadol in two human evoked pain models - the TapCapMentho pilot trial.
Tapentadol is effective in the treatment of neuropathic and nociceptive pain and in acute and chronic pain conditions; two mechanisms combining opioid µ-receptor agonism and noradrenergic reuptake inhibition underlie its analgesic effect. ⋯ The discrepancy between pain models using healthy volunteers and drug trials under real acute and chronic pain conditions in patients as well as methodological aspects may have contributed to this result. The impact of these findings questions the general use of pain models as predictors for early decision making during drug development. The study was registered in ClinicalTrials.gov (NCT01615510).
-
Randomized Controlled Trial
Effects of Different Anesthetics on Pain Processing in an Experimental Human Pain Model.
After surgical procedures, anesthesia itself may affect pain perception. Particularly, there is increasing evidence that opioids not only have analgesic effects but also provoke pronociceptive changes, that is, opioid-induced hyperalgesia. We investigated the effect of different anesthetic regimens on pain processing in volunteers using a transdermal electrical pain model. In this model, stimulation of epidermal nerve fibers representing mainly peptidergic C-nociceptors leads to secondary hyperalgesia and habituation to the stimulus. ⋯ The results suggest a short-term analgesic effect of general anesthesia. Furthermore, the conditioning stimulation over several days induced differential modulation of pro- and antinociceptive systems.
-
Randomized Controlled Trial
A Randomized, Double-blind, Positive-controlled, 3-way Cross-over Human Experimental Pain Study of a TRPV1 Antagonist (V116517) in Healthy Volunteers and Comparison with Preclinical Profile.
This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. ⋯ The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue.