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The loss of descending inhibitory control is thought critical to the development of chronic pain but what causes this loss in function is not well understood. We have investigated the dynamic contribution of prelimbic cortical neuronal projections to the periaqueductal grey (PrL-P) to the development of neuropathic pain in rats using combined opto- and chemo-genetic approaches. We found PrL-P neurons to exert a tonic inhibitory control on thermal withdrawal thresholds in uninjured animals. Following nerve injury, ongoing activity in PrL-P neurons masked latent hypersensitivity and improved affective state. However, this function is lost as the development of sensory hypersensitivity emerges. Despite this loss of tonic control, opto-activation of PrL-P neurons at late post-injury timepoints could restore the anti-allodynic effects by inhibition of spinal nociceptive processing. We suggest that the loss of cortical drive to the descending pain modulatory system underpins the expression of neuropathic sensitisation after nerve injury.
Learn More >Controlling receptor functional selectivity profiles for opioid receptors is a promising approach for discovering safer analgesics; however, the structural determinants conferring functional selectivity are not well understood. Here we used crystal structures of opioid receptors, including the recently solved active state kappa opioid complex with MP1104, to rationally design novel mixed mu (MOR) and kappa (KOR) opioid receptor agonists with reduced arrestin signaling. Analysis of structure-activity relationships for new MP1104 analogs points to a region between transmembrane 5 (TM5) and extracellular loop (ECL2) as key for modulation of arrestin recruitment to both MOR and KOR. The lead compounds, MP1207 and MP1208, displayed MOR/KOR Gi-partial agonism with diminished arrestin signaling, showed efficient analgesia with attenuated liabilities, including respiratory depression and conditioned place preference and aversion in mice. The findings validate a novel structure-inspired paradigm for achieving beneficial profiles for analgesia through different mechanisms that include bias, partial agonism, and dual MOR/KOR agonism.
Learn More >β-arrestin2 recruitment to μ receptors may contribute to the development opioid analgesics side effects. This possibility led to the development of TRV130 and PZM21, opioids reportedly biased against β-arrestin2 recruitment in favour of G protein signalling. However, low efficacy for β-arrestin2 recruitment by TRV130 and PZM21 may simply reflect partial agonism overlooked due to the overexpression of μ receptors.
Learn More >Nociception and opioid antinociception in females are pliable processes, varying qualitatively and quantitatively over the reproductive cycle. Spinal estrogenic signaling via membrane estrogen receptors (mERs), in combination with multiple other signaling molecules [spinal dynorphin, kappa-opioid receptors (KOR), glutamate and metabotropic glutamate receptor 1 (mGluR)], appears to function as a master coordinator, parsing functionality between pronociception and antinociception. This provides a window into pharmacologically accessing intrinsic opioid analgesic/anti-allodynic systems. In diestrus, membrane estrogen receptor alpha (mERα) signals via mGluR to suppress spinal endomorphin 2 (EM2) analgesia. Strikingly, in the absence of exogenous opioids, interfering with this suppression in a chronic pain model elicits opioid anti-allodynia, revealing contributions of endogenous opioid(s). In proestrus, robust spinal EM2 analgesia is manifest but this requires spinal dynorphin/KOR and glutamate-activated mGluR. Furthermore, spinal mGluR blockade in a proestrus chronic pain animal (eliminating spinal EM2 analgesia) exacerbates mechanical allodynia, revealing tempering by endogenous opioid(s). A complex containing mu-opioid receptor, KOR, aromatase, mGluRs, and mERα are foundational to eliciting endogenous opioid anti-allodynia. Aromatase-mERα oligomers are also plentiful, in a central nervous system region-specific fashion. These can be independently regulated and allow estrogens to act intracellularly within the same signaling complex in which they are synthesized, explaining asynchronous relationships between circulating estrogens and central nervous system estrogen functionalities. Observations with EM2 highlight the translational relevance of extensively characterizing exogenous responsiveness to endogenous opioids and the neuronal circuits that mediate them along with the multiplicity of estrogenic systems that concomitantly function in phase and out-of-phase with the reproductive cycle.
Learn More >This report describes the development of an orally active analgesic that resolves inflammation and neuropathic pain without the addictive potential of opioids. EC5026 acts on the cytochrome P450 branch of the arachidonate cascade to stabilize epoxides of polyunsaturated fatty acids (EpFA), which are natural mediators that reduce pain, resolve inflammation, and maintain normal blood pressure. EC5026 is a slow-tight binding transition-state mimic that inhibits the soluble epoxide hydrolase (sEH) at picomolar concentrations. The sEH rapidly degrades EpFA; thus, inhibiting sEH increases EpFA and confers beneficial effects. This mechanism addresses disease states by shifting endoplasmic reticulum stress from promoting cellular senescence and inflammation toward cell survival and homeostasis. We describe the synthesis and optimization of EC5026 and its development through human Phase 1a trials with no drug-related adverse events. Additionally, we outline fundamental work leading to discovery of the analgesic and inflammation-resolving CYP450 branch of the arachidonate cascade.
Learn More >Peripheral sensory neurons are characterized by their size, molecular profiles, and physiological responses to specific stimuli. In mouse, the peptidergic and non-peptidergic subsets of nociceptors are distinct and innervate different lamina of the spinal dorsal horn. The unique molecular signature and neuroanatomical organization of these neurons supports a labeled line theory for certain types of nociceptive stimuli. However, long standing evidence supports the polymodal nature of nociceptors in many species. We have recently shown that the peptidergic marker, CGRP, and the non-peptidergic marker, P2X3R, show largely overlapping expression at the mRNA level in human dorsal root ganglion (DRG). Herein, our aim was to assess the protein distribution of nociceptor markers, including their central projections, in the human DRG and spinal cord. Using DRGs obtained from organ donors, we observed that CGRP and P2X3R were co-expressed by approximately 33% of human DRG neurons and TrpV1 was expressed in ~60% of human DRG neurons. In the dorsal spinal cord, CGRP, P2X3R, TrpV1 and Nav1.7 protein stained the entirety of lamina 1-2, with only P2XR3 showing a gradient of expression. This was confirmed by measuring the size of the substantia gelatinosa using Hematoxylin and Eosin staining of adjacent sections. Our findings are consistent with the known polymodal nature of most primate nociceptors and indicate that the central projection patterns of nociceptors are different between mice and humans. Elucidating how human nociceptors connect to subsets of dorsal horn neurons will be important for understanding the physiological consequences of these species differences. This article is protected by copyright. All rights reserved.
Learn More >Central post-stroke pain is a chronic neuropathic pain syndrome following a cerebrovascular accident. The development of central post-stroke pain is estimated to occur in 8 to 55% of stroke patients and is described as constant or intermittent neuropathic pain accompanied by dysesthesia of temperature and/or pressure sensations. These pain and sensory deficits are within the area of the body corresponding to the stroke lesion. The onset of pain is usually gradual, though it can develop either immediately after stroke or years after. Given the diversity in its clinical presentation, central post-stroke pain is a challenging diagnosis of exclusion. Furthermore, central post-stroke pain is often resistant to pharmacological treatment options and a clear therapeutic algorithm has not been established. Based on current evidence, amitriptyline, lamotrigine, and gabapentinoids should be used as first-line pharmacotherapy options when central post-stroke pain is suspected. Other drugs, such as fluvoxamine, steroids, and Intravenous infusions of lidocaine, ketamine, or even propofol, can be considered in intractable cases. In addition, interventional therapies such as motor cortex stimulation or transcranial magnetic stimulation have been shown to provide relief in difficult-to-treat patients.
Learn More >This systematic review aimed to 1) assess associations between psychological factors and pain after breast cancer (BC) treatment and 2) determine which preoperative psychological factors predicted pain in the acute, subacute, and chronic time frames after BC surgery.
Learn More >The nervous system plays important roles in homeostasis and inflammatory responses in tissues. However, the regulation of lymph nodes (LN) by nerves remains largely unknown. Huang et al. demonstrate that LNs are innervated by unique peptidergic nociceptors that signal to various endothelial, stromal, and immune cell types in LNs.
Learn More >Galcanezumab, a humanized monoclonal antibody that binds calcitonin gene-related peptide, has demonstrated a significant reduction in monthly migraine headache days compared with placebo. Here, we analyze data from 3 randomized clinical trials (2 episodic trials [EVOLVE-1, EVOLVE-2] and 1 chronic trial [REGAIN]), to examine if galcanezumab also alleviates the severity and symptoms of migraine.
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