Browse by Audience
Non-opioid therapeutics for the treatment of neuropathic pain are urgently needed to address the ongoing opioid crisis. Peptides from cone snail venoms have served as invaluable molecules to target key pain-related receptors but can suffer from unfavorable physicochemical properties, which limit their therapeutic potential. In this work, we developed conformationally constrained α-RgIA analogues with high potency, receptor selectivity and enhanced serum stability to target the human α9α10 nicotinic acetylcholine receptor. The key lactam linkage introduced in α-RgIA fixed the favored globular conformation and suppressed disulfide scrambling. The NMR structure of the macrocyclic peptide overlays well with that of α-RgIA4, demonstrating that the cyclization does not perturb the overall conformation of backbone and key side-chain residues. Finally, a molecular docking model was used to rationalize the selective binding between a macrocyclic analogue and the α9α10 nicotinic acetylcholine receptor. These conformationally constrained antagonists are therefore promising candidates for antinociceptive therapeutic intervention.
Learn More >The orbitofrontal cortex (OFC) plays a critical role in evaluating outcomes in a changing environment. Administering opioids to the OFC can alter the hedonic reaction to food rewards and increase their consumption in a subregion specific manner. However, it is unknown how mu-opioid signalling influences synaptic transmission in the OFC. Thus, we investigated the cellular actions of mu-opioids within distinct subregions of the OFC. Using in-vitro patch clamp electrophysiology in brain slices containing the OFC, we found that the mu-opioid agonist, DAMGO produced a concentration-dependant inhibition of GABAergic synaptic transmission onto medial OFC (mOFC), but not lateral OFC (lOFC) neurons. This effect was mediated by presynaptic mu-opioid receptor activation of local parvalbumin (PV+)-expressing interneurons. The DAMGO-induced suppression of inhibition was long-lasting and not reversed upon washout of DAMGO, or by application of the mu-opioid receptor antagonist, CTAP, suggesting an inhibitory long-term depression (iLTD) induced by an exogenous mu-opioid. We show that LTD at inhibitory synapses is dependent on downstream cAMP/PKA signaling, which differs between the mOFC and lOFC. Finally, we demonstrate that endogenous opioid release triggered via moderate physiological stimulation can induce LTD. Taken together, these results suggest that presynaptic mu-opioid stimulation of local PV+ interneurons induces a long-lasting suppression of GABAergic synaptic transmission, which depends on subregional differences in mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascade. These findings provide mechanistic insight into the opposing functional effects produced by mu-opioids within the OFC.Considering that both the OFC and the opioid system regulate reward, motivation, and food intake; understanding the role of opioid signaling within the OFC is fundamental for a mechanistic understanding of the sequelae for several psychiatric disorders. This study makes several novel observations. First, mu-opioids induce a long-lasting suppression of inhibitory synaptic transmission onto OFC pyramidal neurons in a regionally selective manner. Secondly, mu-opioids recruit PV+ inputs to suppress inhibitory synaptic transmission in the mOFC. Thirdly, the regional selectivity of mu-opioid action of endogenous opioids is due to the efficacy of mu-opioid receptor coupling to the downstream cAMP/PKA intracellular cascades. These experiments are the first to reveal a cellular mechanism of opioid action within the OFC.
Learn More >Chemotherapy-induced peripheral neuropathy is a serious adverse effect of chemotherapeutic agents such as paclitaxel. JTC-801, a nociceptin/orphanin FQ opioid peptide (NOP) receptor antagonist, has been reported to attenuate neuropathic pain in several pain models. However, the therapeutic significance and function of JTC-801 in chemotherapy-induced peripheral neuropathy remain unclear. In this study, we determined the effect of JTC-801 on neuropathic pain induced by paclitaxel, and we explored the potential mechanism in the dorsal root ganglion (DRG). The behavioral test showed that single or multiple systemic administrations of JTC-801 significantly alleviated mechanical allodynia in paclitaxel-treated rats. Using Western blot analysis and immunohistochemistry, we found that paclitaxel increased the expression of phosphatidylinositol 3-kinase (PI3K) and phospho-Akt (p-Akt) in the DRG. Double immunofluorescence staining indicated that p-Akt was expressed in neurons in the DRG. Multiple injections of JTC-801 significantly inhibited the activation of Akt and decreased the expression of inflammatory cytokines. The data suggest that JTC-801 alleviates mechanical allodynia associated with paclitaxel-induced neuropathic pain via the PI3K/Akt pathway.
Learn More >Adequate analgesia can be challenging, as pharmacological options are not necessarily effective for all types of pain and are associated with adverse effects. Methadone is increasingly being considered in the management of both cancer-related and non-cancer-related pain. The purpose of this article is to provide a narrative review of all available randomized controlled trials (RCT) investigating the effectiveness of methadone in the management of pain, in relation to a comparison drug. The primary outcome was analgesic effectiveness, and the secondary outcomes were side effects and cost. A search of PubMed, Medline, Embase, and Google Scholar databases was conducted to identify eligible RCTs and methodologic quality was assessed. A total of 40 RCTs were included in this review. The majority compared methadone to morphine or fentanyl. Analgesic effectiveness of methadone was demonstrated in different types of pain, including post-procedural, cancer-related, nociceptive, and neuropathic pain. The evidence demonstrates that the use of methadone in post-procedural pain and in cancer-related pain may be dependent on the procedure and cancer type, respectively. Side effects experienced were generally similar to the comparison drug, and lower cost was a benefit to using methadone. Methadone may also be useful as an adjunctive analgesic for adequate pain control, as well as in patients with renal impairment. Additional high quality large-scale RCT evidence is needed to establish its role as monotherapy or as an adjunctive medication. Future research should also aim to standardize reported outcomes for measuring analgesic effectiveness to permit for pooled analysis across studies. PERSPECTIVE: This article presents a systematic review, which includes a summary of published randomized controlled trials investigating the effectiveness of methadone in the management of pain. This is important for determining its analgesic utility and for identifying gaps in existing knowledge.
Learn More >Introduction Neuropathic pain disorders are diverse, and the currently available therapies are ineffective in the majority of cases. Therefore, there is a major need for gaining novel mechanistic insights and developing new treatment strategies for neuropathic pain. Areas covered We performed an in-depth literature search on the molecular mechanisms and systemic importance of the ceramide-to-S1P rheostat regulating neuron function and neuroimmune interactions in the development of neuropathic pain. Expert Opinion The S1P receptor modulator FTY720 (fingolimod, Gilenya®), LPA receptor antagonists and several mechanistically related compounds in clinical development raise great expectations for treating neuropathic pain disorders. Research on S1P receptors, S1P receptor modulators or SPHK inhibitors with distinct selectivity, pharmacokinetics and safety must provide more mechanistic insight into whether they may qualify as useful treatment options for neuropathic pain disorders. The functional relevance of genetic variations within the ceramide to S1P rheostat should be explored for an enhanced understanding of neuropathic pain pathogenesis. The ceramide to S1P rheostat is emerging as a critically important regulator hub of neuroimmune interactions along the pain pathway, and improved mechanistic insight is required to develop more precise and effective drug treatment options for patients suffering from neuropathic pain disorders.
Learn More >To investigate the formulation of the peptide-based antagonist ( Pro, Phe)CGRP , of the human calcitonin gene-related peptide (CGRP) receptor as a potential nasally delivered migraine treatment.
Learn More >The otic ganglion (OG) provides parasympathetic innervation to the cerebral circulation and cranial structures and may be involved in the pathophysiology of trigeminal autonomic headaches. This structure has never been targeted in any headache disorder.
Learn More >CGRP pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia.
Learn More >Neuronal nicotinic acetylcholine receptor (nAChR)-based therapeutics are sought as a potential alternative strategy to opioids for pain management. In this study, we examine the antinociceptive effects of 3-(2-chlorophenyl)-5-(5-methyl-1-(piperidin-4-yl)-1-pyrazol-4-yl)isoxazole (CMPI), a novel positive allosteric modulator (PAM), with preferential selectivity to the low agonist sensitivity (α4)3(β2)2 nAChR and desformylflustrabromine (dFBr), a PAM for α4-containing nAChRs. We used hot plate and tail flick tests to measure the effect of dFBr and CMPI on the latency to acute thermal nociceptive responses in rats. Intraperitoneal injection of dFBr, but not CMPI, dose-dependently increased latency in the hot plate test. In the tail flick test, the effect achieved at the highest dFBr or CMPI dose tested was only <20% of the maximum possible effects reported for nicotine and other nicotinic agonists. Moreover, the coadministration of dFBr did not enhance the antinociceptive effect of a low dose of nicotine. Our results show that the direct acute effect of dFBr is superior to that for CMPI, indicating that selectivity to (α4)3(β2)2 nAChR is not advantageous in alleviating responses to acute thermal nociceptive stimulus. However, further studies are necessary to test the suitability of (α4)3(β2)2 nAChR-selective PAMs in chronic pain models.
Learn More >The α9α10 nicotinic acetylcholine receptor (nAChR) has been characterized as an effective anti-pain target that functions through a non-opioid mechanism. However, as a pentameric ion channel comprised of two different subunits, the specific targeting of α9α10 nAChRs has proven challenging. Previously the 13-amino-acid peptide, RgIA, was shown to block α9α10 nAChRs with high potency and specificity. This peptide, characterized from the venom of the carnivorous marine snail, Conus regius, produced analgesia in several rodent models of chronic pain. Despite promising pre-clinical data in behavioral assays, the number of specific α9α10 nAChR antagonists remains small and the physiological mechanisms of analgesia remain cryptic. In this study, we implement amino-acid substitutions to definitively characterize the chemical properties of RgIA that contribute to its activity against α9α10 nAChRs. Using this mutational approach, we determined the vital role of biochemical side-chain properties and amino acids in the second loop that are amenable to substitutions to further engineer next-generation analogs for the blockade of α9α10 nAChRs.
Learn More >