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The specific mechanism of migraine chronification remains unclear. We previously demonstrated that synaptic plasticity was associated with migraine chronification. EphB receptors and their ligands, ephrinBs, are considered to be key molecules regulating the synaptic plasticity of the central nervous system. However, whether they can promote the chronification of migraine by regulating synaptic plasticity is unknown. Therefore, we investigated the role of ephrinB/EphB signaling in chronic migraine (CM). Male Sprague-Dawley rats were used to construct a chronic migraine model by dural infusion of an inflammatory soup for 7 days. We used qPCR, western blot, and immunofluorescence to detect the mRNA and protein levels of EphB2 and ephrinB2. The paw withdrawal latency and paw withdrawal threshold were measured after lateral ventricle treatment with EphB1-Fc (an inhibitor of EphB receptor). Changes in synaptic plasticity were explored by examining synaptic-associated proteins by western blot, dendritic spines of neurons by Golgi-Cox staining, and synaptic ultrastructure by transmission electron microscopy. We found that the expression of EphB2 and ephrinB2 was increased in CM. The administration of EphB1-Fc relieved hyperalgesia and changes in synaptic plasticity induced by CM. In addition, EphB1-Fc inhibited the upregulation of NR2B phosphorylation. These results indicate that ephrinB/EphB signaling may regulate synaptic plasticity in CM via NR2B phosphorylation, which suggests the novel idea that ephrinB/EphB signaling may be a target for the treatment of migraine chronification.
Learn More >In osteoarthritis (OA), the pain-structure relationship remains complex and poorly understood. Here, we used the mechanical joint loading (MJL) model of OA to investigate both knee pathology and nociceptive behaviour.
Learn More >Chemotherapy induced peripheral neuropathy (CIPN), a toxic side effect of some cancer treatments, negatively impacts patient outcomes and drastically reduces survivor's quality of life (QOL). Uncovering the mechanisms driving chemotherapy-induced CIPN is urgently needed to facilitate the development of effective treatments, as currently there are none. Observing that C57BL/6 (B6) and 129SvEv (129) mice are respectively sensitive and resistant to Paclitaxel-induced pain, we investigated the involvement of the gut microbiota in this extreme phenotypic response. Reciprocal gut microbiota transfers between B6 and 129 mice as well as antibiotic depletion causally linked gut microbes to Paclitaxel-induced pain sensitivity and resistance. Microglia proliferated in the spinal cords of Paclitaxel treated mice harboring the pain-sensitive B6 microbiota but not the pain-resistant 129 microbiota, which exhibited a notable absence of infiltrating immune cells. Paclitaxel decreased the abundance of Akkermansia muciniphila, which could compromise barrier integrity resulting in systemic exposure to bacterial metabolites and products – that acting via the gut-immune-brain axis – could result in altered brain function. Other bacterial taxa that consistently associated with both bacteria and pain as well as microglia and pain were identified, lending support to our hypothesis that microglia are causally involved in CIPN, and that gut bacteria are drivers of this phenotype.
Learn More >The aim of this systematic review was to summarize the effects of physical exercise on neuropathic pain (NP) in animal models of SCI. The search was conducted in Medline and Science Direct to identify experimental pre-clinical studies involving animal models of SCI, physical exercise as an intervention and the assessment of NP. Fifteen articles met the eligibility criteria. The review shows that in studies of NP involving animal models of SCI, rodents are the most common species. Thoracic contusion is the most common injury and mechanical and thermal nociception are the most frequently assessed NP components. The benefits of physical exercise vary according to its starting period and total duration. In addition, there is considerable heterogeneity regarding the type and intensity of exercise capable of alleviating NP after SCI. Furthermore, physical exercise has beneficial effects on mechanical, thermal and cold nociception, and spontaneous pain. These results are weakened by the paucity of studies involving these pain outcomes. The review protocol is published for free access on the SyRF platform (http://syrf.org.uk/protocols/).
Learn More >Distinct types of dorsal root ganglion sensory neurons may have unique contributions to chronic pain. Identification of primate sensory neuron types is critical for understanding the cellular origin and heritability of chronic pain. However, molecular insights into the primate sensory neurons are missing. Here we classify non-human primate dorsal root ganglion sensory neurons based on their transcriptome and map human pain heritability to neuronal types. First, we identified cell correlates between two major datasets for mouse sensory neuron types. Machine learning exposes an overall cross-species conservation of somatosensory neurons between primate and mouse, although with differences at individual gene level, highlighting the importance of primate data for clinical translation. We map genomic loci associated with chronic pain in human onto primate sensory neuron types to identify the cellular origin of chronic pain. Genome-wide associations for chronic pain converge on two different neuronal types distributed between pain disorders that display different genetic susceptibilities, suggesting both unique and shared mechanisms between different pain conditions.
Learn More >Electroconvulsive therapy (ECT) has been applied for chronic pain for decades. The amounts of opioids to treat pain are sometimes reduced after a series of ECT. The effect of ECT on morphine-induced analgesia and its mechanism underlying the reduction of morphine requirement has yet to be clarified. Therefore, we administered electroconvulsive shocks (ECS) to mice and investigated the antinociceptive effect of morphine in a hot plate test. We examined the expression level of µ-opioid receptor in the thalami of mice 25 h after administration of ECS compared to the thalami of mice without ECS administration using western blotting. ECS disturbed the development of a decrease in the percentage of maximal possible effect (%MPE), which was observed 24 h after a morphine injection, when ECS was applied 25, 23, 21, and 12 h before the second administration of morphine. We also examined the effect of ECS on the dose-response curve of %MPE to morphine-antinociception. Twenty-five hours after ECS, the dose-response curve was shifted to the left, and the EC of morphine given to ECS-pretreated mice decreased by 30.1% compared to the mice that were not pretreated with ECS. We also found that the expression level of µ-opioid receptors was significantly increased after ECS administration. These results confirm previous clinical reports showing that ECT decreased the required dose of opioids in neuropathic pain patients and suggest the hypothesis that this effect of ECT works through the thalamus.
Learn More >Stress facilitates pain perception and sensitizes pain pathways，but the underlying mechanism is still unclear. The purpose of this study was to investigate whether activation of 5-hydroxytryptamine (5-HT) subtype-3 receptor in the spinal cord contributes to somatic hyperalgesia induced by repeated 3 day forced swim (FS) in the estradiol (E2) replacement rats after ovariectomy (OVx). Somatic sensitivity was assessed by thermal withdrawal latency to radiant heat and mechanical withdrawal threshold to von Frey filaments. The expression of 5-HT3A receptor in the L4-L5 dorsal spinal cord was examined by Western blot. Repeated FS stress reduced the thermal withdrawal latency and mechanical withdrawal threshold, and the presence of E2 exaggerated this hyperalgesia. The expression of 5-HT3A receptor in the L4-L5 dorsal spinal cord increased significantly following repeated FS in E2 replacement rats. Intrathecal injection of 5-HT3 receptor antagonist Y-25130 blocked the somatic hyperalgesia induced by FS stress. These data indicate that 5-HT3 receptor activation through the descending facilitation system contributes to the somatic hyperalgesia evoked by FS stress. The results may provide a new therapeutic avenue for alleviating pain induced by stress.
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 >Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
Learn More >Although TWIK-related spinal cord K (TRESK) channel is expressed in all primary afferent neurons in trigeminal ganglia (TG) and dorsal root ganglia (DRG), whether TRESK activity regulates trigeminal pain processing is still not established. Dominant-negative TRESK mutations are associated with migraine but not with other types of pain in humans, suggesting that genetic TRESK dysfunction preferentially affects the generation of trigeminal pain, especially headache. Using TRESK global knockout mice as a model system, we found that loss of TRESK in all TG neurons selectively increased the intrinsic excitability of small-diameter nociceptors, especially those that do not bind to isolectin B4 (IB4). Similarly, loss of TRESK resulted in hyper-excitation of the small IB4 dural afferent neurons but not those that bind to IB4 (IB4). Compared with wild-type littermates, both male and female TRESK knockout mice exhibited more robust trigeminal nociceptive behaviors, including headache-related behaviors; whereas their body and visceral pain responses were normal. Interestingly, neither the total persistent outward current nor the intrinsic excitability was altered in adult TRESK knockout DRG neurons, which may explain why genetic TRESK dysfunction is not associated with body and/or visceral pain in humans. We reveal for the first time that, among all primary afferent neurons, TG nociceptors are the most vulnerable to the genetic loss of TRESK. Our findings indicate that endogenous TRESK activity regulates trigeminal nociception, likely through controlling the intrinsic excitability of TG nociceptors. Importantly, we provide evidence that genetic loss of TRESK significantly increases the likelihood of developing headache. TRESK K channel is expressed in all primary afferent neurons in trigeminal ganglia (TG) and dorsal root ganglia (DRG), but dominant-negative TRESK mutations are only associated with migraine but not with other types of pain in humans. In TRESK global knockout mice, we found that ubiquitous loss of TRESK selectively increased the intrinsic excitability of small-diameter TG nociceptors without affecting DRG neuronal excitability. Compared with wild-type littermates, TRESK knockout mice exhibited more robust trigeminal pain, especially headache-related behaviors; whereas their body and visceral pain responses were normal. This recapitulates the clinical manifestations of human TRESK mutations. Our results indicate that endogenous TRESK activity regulates trigeminal nociception, and genetic loss of TRESK significantly increases the likelihood of developing headache.
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