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Post-traumatic headache (PTH) is one of the most common, debilitating and difficult symptoms to manage after a traumatic head injury. While the mechanisms underlying PTH remain elusive, recent studies in rodent models suggest the potential involvement of calcitonin gene-related peptide (CGRP), a mediator of neurogenic inflammation, and the ensuing activation of meningeal mast cells (MCs), pro-algesic resident immune cells that can lead to the activation of the headache pain pathway. Here, we investigated the relative contribution of MCs to the development of PTH-like pain behaviors in a model of mild closed head injury (mCHI) in male rats. We initially tested the relative contribution of peripheral CGRP signaling to the activation of meningeal MCs following mCHI using a blocking anti-CGRP monoclonal antibody. We then employed a prophylactic MC granule depletion approach to address the hypotheses that intact meningeal MC granule content is necessary for the development of PTH-related pain-like behaviors. The data suggest that following mCHI, ongoing activation of meningeal MCs is not mediated by peripheral CGRP signaling, and does not contribute to the development of the mCHI-evoked cephalic mechanical pain hypersensitivity. Our data, however, also reveals that the development of latent sensitization, manifested as persistent hypersensitivity upon the recovery from mCHI-evoked acute cranial hyperalgesia to the headache trigger glyceryl trinitrate requires intact MC content during and immediately after mCHI. Collectively, our data implicate the acute activation of meningeal MCs as mediator of chronic pain hypersensitivity following a concussion or mCHI. Targeting MCs may be explored for early prophylactic treatment of PTH.
Learn More >To investigate the associations between signs of painful temporomandibular disorders (TMD) and number of tender points (TPs) and fibromyalgia in adolescents, as well as the relationship between TPs and pressure-pain threshold (PPT) in individuals presenting with local, regional, or widespread pain as a way to investigate the presence of central sensitization (CS).
Learn More >If touch is perceived as pleasant, it can counteract the experience of pain. However, its pain-inhibitory function might be disturbed in chronic pain and this could contribute to pain-related interference. We investigated the perception of pleasant touch and its brain correlates in chronic back pain patients (CBP) compared to subacute back pain patients (SABP) and healthy controls (HC) using soft brush strokes. CBP showed less positive evaluations of touch. We found the highest activation in somatosensory and insular cortices in CBP, ventral striatum (VS) in SABP, and the orbitofrontal cortex in HC. Brain responses were significantly positively correlated with pleasantness ratings in HC and SABP, but not CBP. Further, the insula responses in CBP were positively correlated with pain-related interference and the VS activation in SABP correlated negatively with affective distress. Brain and behavioral changes in the processing of touch and its pleasantness may be a marker of pain chronicity and raise questions about the therapeutic value of pleasant touch in pain prevention and treatment.
Learn More >Over 100 million people are challenged by the effects of chronic pain in the United States alone. This burden also impacts the U.S. economy; 600 billion dollars annually is spent on medical care, medications, and lost productivity in the workplace.1 Current opioid treatments cause adverse effects including nausea, constipation, tolerance, and addiction liability.2 Nociceptive sensitization is thought to perpetuate chronic pain, but too little is known about its mechanisms. Components of the pathways that sensitize the nociceptors after injury are likely to be valuable targets for novel medications for the relief or prevention of chronic pain. Utilizing the Drosophila melanogaster cell targeting and RNA interference toolkit, we are investigating the Bone Morphogenetic Protein (BMP) pathway and its role in ultraviolet light (UV) injury-induced nociceptive sensitization. BMPs are well known as secreted developmental morphogens that control development, but other functions are known.3 We have previously identified BMP signaling components used in nociceptors to modulate injury-induced allodynia, including Decapentaplegic (Dpp, orthologous to mammalian BMP 2/4), and its downstream signaling components.4 The morphogen Hedgehog has also been shown to be necessary for allodynia following injury.5 Here, we show that two membrane-embedded regulators of the Dpp and Hedgehog pathways, Dally and Dally-like, are necessary for injury-induced thermal allodynia, as the formation of sensitization was reduced when either component was suppressed. These BMP components are highly conserved and, because dysregulation of nociceptor sensitization underlies chronic pain, the homologs of Dally and Dally-like may represent novel therapeutic targets in humans challenged by chronic pain. Furthermore, because of their extracellular location, Dally and Dally-like represent attractive therapeutic drug targets because such drugs would not need to cross the plasma membrane.
Learn More >The box jellyfish Chironex fleckeri is extremely venomous, and envenoming causes tissue necrosis, extreme pain and death within minutes after severe exposure. Despite rapid and potent venom action, basic mechanistic insight is lacking. Here we perform molecular dissection of a jellyfish venom-induced cell death pathway by screening for host components required for venom exposure-induced cell death using genome-scale lenti-CRISPR mutagenesis. We identify the peripheral membrane protein ATP2B1, a calcium transporting ATPase, as one host factor required for venom cytotoxicity. Targeting ATP2B1 prevents venom action and confers long lasting protection. Informatics analysis of host genes required for venom cytotoxicity reveal pathways not previously implicated in cell death. We also discover a venom antidote that functions up to 15 minutes after exposure and suppresses tissue necrosis and pain in mice. These results highlight the power of whole genome CRISPR screening to investigate venom mechanisms of action and to rapidly identify new medicines.
Learn More >Recently studies have focused on the anti-hyperalgesic activity of the A3 adenosine receptor (A3AR) in several chronic pain models, but the cellular and molecular basis of this effect is still unknown. Here, we investigated the expression and functional effects of A3AR on the excitability of small-medium sized, capsaicin-sensitive, dorsal root ganglion (DRG) neurons isolated from 3-4 week-old rats. RT-PCR experiments and immunofluorescence analysis revealed A3AR expression in DRG neurons. Patch-clamp experiments demonstrated that two distinct A3AR agonists, Cl-IB-MECA and the highly selective MRS5980, inhibited Ca-activated K (KCa) currents evoked by a voltage ramp protocol. This effect was dependent on a reduction of Ca influx via N-type voltage-dependent Ca channels (VDCCs) as Cl-IB-MECA-induced inhibition was sensitive to the N-type blocker PD173212 but not to the L-type blocker, lacidipine. The endogenous agonist adenosine also reduced N-type Ca currents, and its effect was inhibited by 56% in the presence of A3AR antagonist MRS1523, demonstrating that the majority of adenosine's effect is mediated by this receptor subtype. Current-clamp recordings demonstrated that neuronal firing of rat DRG neurons was also significantly reduced by A3AR activation in a MRS1523-sensitive but PD173212-insensitive manner. Intracellular Ca measurements confirmed the inhibitory role of A3AR on DRG neuronal firing. We conclude that pain-relieving effects observed upon A3AR activation could be mediated through N-type Ca channel block and action potential inhibition as independent mechanisms in isolated rat DRG neurons. These findings support A3AR-based therapy as a viable approach to alleviate pain in different pathologies.
Learn More >The relationship between gut microbiota and neurological diseases, including chronic pain, has received increasing attention. The gut microbiome is a crucial modulator of visceral pain, whereas recent evidence suggests that gut microbiota may also play a critical role in many other types of chronic pain, including inflammatory pain, headache, neuropathic pain, and opioid tolerance. We present a narrative review of the current understanding on the role of gut microbiota in pain regulation and discuss the possibility of targeting gut microbiota for the management of chronic pain. Numerous signalling molecules derived from gut microbiota, such as by-products of microbiota, metabolites, neurotransmitters, and neuromodulators, act on their receptors and remarkably regulate the peripheral and central sensitisation, which in turn mediate the development of chronic pain. Gut microbiota-derived mediators serve as critical modulators for the induction of peripheral sensitisation, directly or indirectly regulating the excitability of primary nociceptive neurones. In the central nervous system, gut microbiota-derived mediators may regulate neuroinflammation, which involves the activation of cells in the blood-brain barrier, microglia, and infiltrating immune cells, to modulate induction and maintenance of central sensitisation. Thus, we propose that gut microbiota regulates pain in the peripheral and central nervous system, and targeting gut microbiota by diet and pharmabiotic intervention may represent a new therapeutic strategy for the management of chronic pain.
Learn More >This longitudinal case-control study aims to 1) compare symptoms and functioning in otherwise healthy adolescents with versus without a parent with chronic pain (Parent CP+/Parent CP-) 2) test adolescent sex as a moderator of the relation between parent CP group and child functioning, and 3) determine changes in adolescent pain over one year. Adolescents (n=140; ages 11-15) completed tests of pain responsivity and physical function, as well as self-report measures assessing pain characteristics, somatic symptoms, and physical and psychosocial functioning. Self-reported pain and somatic symptoms were re-assessed one year later. Adolescents in the Parent CP+ group reported greater pain, somatic symptoms, and worse physical health than Parent CP- youth. Parent CP+ youth performed worse on all tests of physical function. Some observed effects were stronger for girls than boys. There were no differences between groups on pain responsivity. Both groups reported increased pain and somatic symptoms from baseline to one-year follow-up, with the Parent CP+ group reporting the highest level of symptoms at both time points. This study highlights the potential impact of parental pain status on children, particularly daughters, and is the first to document objective physical functioning differences in youth at risk for developing chronic pain. Perspective: Adolescents who have a parent with chronic pain demonstrate higher pain and lower physical function than adolescents who have a parent without chronic pain. Group differences in pain and somatic symptoms persist over one year. Family based interventions are needed for comprehensive pain prevention and treatment.
Learn More >Cisplatin is a widely used platinum-derived antineoplastic agent that frequently results in peripheral neuropathy. Therapeutic strategies for neuropathic pain are limited and characterized by variable efficacy and severe adverse effects. Clinical translation of novel analgesics has proven difficult with many agents demonstrating preclinical efficacy failing in clinical trials. Preclinical studies frequently assess pain behaviors in the hind paws, however the front paws have a greater degree of the fine sensorimotor functions characteristically damaged by chemotherapy-induced neuropathy. This is the first study to assess pain responses in the front paws. Here we test the hypothesis that mouse front paws exhibit pain-related alterations in mechanical and thermal (cold) sensitivity in a murine model of cisplatin-induced neuropathy, and that pharmacological treatment with amitriptyline, gabapentin, ibuprofen and URB937 normalize pain behaviors in the front and hind paws. Cold (acetone withdrawal latencies) and mechanical (von Frey withdrawal thresholds) sensitivity were significantly decreased and increased respectively in both the front and the hind paws following initiation of weekly systemic (intraperitoneal) cisplatin injections (5 mg/kg). For the hind paws, systemic administration of amitriptyline (30 mg/kg), gabapentin (100 mg/kg), ibuprofen (0 -10 mg/kg) or URB937 (0 -10 mg/kg) resulted in a decrease in acetone withdrawal latencies and increase in von Frey withdrawal thresholds with return to normal values at the highest doses tested. For the front paws, return to baseline values for the highest doses was found for cold allodynia but not mechanical allodynia, where the highest doses failed to return to baseline values. These results indicate that mouse front paws exhibit pain-related changes in cisplatin-induced neuropathy and that drug effects can vary based on testing stimulus and location. This suggests that front paw responses across multiple modalities provide reliable and accurate information about pain-related drug effects. Future studies should be aimed at elucidating the mechanisms underlying these differential effects.
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