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This study was designed to investigate the expression of transient receptor potential melastatin 3 (TRPM3) and transient receptor potential vanilloid type 4 (TRPV4) in the trigeminal spinal subnucleus caudalis of a rat model of trigeminal neuralgia (TN). The influence of botulinum toxin type A (BTX-A) on the expression of these channels was also explored. In this study, a model was established involving chronic constriction injury to the infraorbital nerve (ION-CCI), inducing TN. To explore the effects of BTX-A and whether it was dose related, rats were divided randomly into four groups: a control group, an ION-CCI group, a 3 U group, and a 10 U group (which received 3 and 10 U/kg BTX-A injections, respectively). Von Frey hairs were used to determine the pain threshold of the rats. The expression of TRPM3 and TRPV4 in the trigeminal spinal subnucleus caudalis was detected using western blots and immunohistochemistry. The pain thresholds of rats decreased to a minimum 14 days after ION-CCI. Compared with the ION-CCI group, the pain thresholds of the 3 and 10 U groups were significantly higher 4 days after the subcutaneous injection of BTX-A (P<0.05). The expression of TRPM3 and TRPV4 in the ION-CCI group was significantly higher than that in the control group (P<0.05). TRPM3 and TRPV4 expression in the 3 and 10 U groups was significantly lower than that in the ION-CCI group (P<0.05). In conclusion, overexpression of TRPM3 and TRPV4 can jointly mediate the occurrence of mechanical hyperalgesia in TN. The analgesic effects of BTX-A may be related to the inhibition of TRPM3 and TRPV4 expression.
Learn More >Spinal transmission of pruritoceptive (itch) signals requires transneuronal signaling by gastrin-releasing peptide (GRP) produced by a subpopulation of dorsal horn excitatory interneurons. These neurons also express the glutamatergic marker vGluT2, raising the question of why glutamate alone is insufficient for spinal itch relay. Using optogenetics together with slice electrophysiology and mouse behavior, we demonstrate that baseline synaptic coupling between GRP and GRP receptor (GRPR) neurons is too weak for suprathreshold excitation. Only when we mimicked the endogenous firing of GRP neurons and stimulated them repetitively to fire bursts of action potentials did GRPR neurons depolarize progressively and become excitable by GRP neurons. GRPR but not glutamate receptor antagonism prevented this action. Provoking itch-like behavior by optogenetic activation of spinal GRP neurons required similar stimulation paradigms. These results establish a spinal gating mechanism for itch that requires sustained repetitive activity of presynaptic GRP neurons and postsynaptic GRP signaling to drive GRPR neuron output.
Learn More >Chronic inflammatory pain is one of the most common complaints that seriously affects patients' quality of life. Previous studies have demonstrated that the analgesic effect of electroacupuncture (EA) stimulation on inflammatory pain is related to its frequency. In this study, we focused on whether the analgesic effects of EA are related to the period of stimulation. Purinergic receptor P2X3 (P2X3) is involved in the pathological process underlying chronic inflammatory pain and neuropathic pain. We hypothesized that 100 Hz EA stimulation alleviated Freund's complete adjuvant (CFA) induced inflammatory pain via regulating P2X3 expression in the dorsal root ganglion (DRG) and/or spinal cord dorsal horn (SCDH). We also assumed that the analgesic effect of EA might be related to the period of stimulation. We found that both short-term (three day) and long-term (14 day) 100 Hz EA stimulation effectively increased the paw withdrawal threshold (PWT) and reversed the elevation of P2X3 in the DRG and SCDH of CFA rats. However, the analgesic effects of 100 Hz EA were not dependent on the period of stimulation. Moreover, P2X3 inhibition or activation may contribute to or attenuate the analgesic effects of 100 Hz EA on CFA-induced inflammatory pain. This result indicated that EA reduced pain hypersensitivity through P2X3 modulation.
Learn More >Unremitting head and neck pain (UHNP) is a commonly encountered phenomenon in Headache Medicine and may be seen in the setting of many well-defined headache types. The prevalence of UHNP is not clear, and establishing the presence of UHNP may require careful questioning at repeated patient visits. The cause of UHNP in some patients may be compression of the lesser and greater occipital nerves by the posterior cervical muscles and their fascial attachments at the occipital ridge with subsequent local perineural inflammation. The resulting pain is typically in the sub-occipital and occipital location, and, via anatomic connections between extracranial and intracranial nerves, may radiate frontally to trigeminal-innervated areas of the head. Migraine-like features of photophobia and nausea may occur with frontal radiation. Occipital allodynia is common, as is spasm of the cervical muscles. Patients with UHNP may comprise a subgroup of Chronic Migraine, as well as of Chronic Tension-Type Headache, New Daily Persistent Headache and Cervicogenic Headache. Centrally acting membrane-stabilizing agents, which are often ineffective for CM, are similarly generally ineffective for UHNP. Extracranially-directed treatments such as occipital nerve blocks, cervical trigger point injections, botulinum toxin and monoclonal antibodies directed at calcitonin gene related peptide, which act primarily in the periphery, may provide more substantial relief for UHNP; additionally, decompression of the occipital nerves from muscular and fascial compression is effective for some patients, and may result in enduring pain relief. Further study is needed to determine the prevalence of UHNP, and to understand the role of occipital nerve compression in UHNP and of occipital nerve decompression surgery in chronic head and neck pain.
Learn More >KCC2 regulates neuronal transmembrane chloride gradients and thereby controls GABA signaling in the brain. KCC2 downregulation is observed in numerous neurological and psychiatric disorders. Paradoxical, excitatory GABA signaling is usually assumed to contribute to abnormal network activity underlying the pathology. We tested this hypothesis and explored the functional impact of chronic KCC2 downregulation in the rat dentate gyrus. Although the reversal potential of GABAA receptor currents is depolarized in KCC2 knockdown neurons, this shift is compensated by depolarization of the resting membrane potential. This reflects downregulation of leak potassium currents. We show KCC2 interacts with Task-3 (KCNK9) channels and is required for their membrane expression. Increased neuronal excitability upon KCC2 suppression altered dentate gyrus rhythmogenesis, which could be normalized by chemogenetic hyperpolarization. Our data reveal KCC2 downregulation engages complex synaptic and cellular alterations beyond GABA signaling that perturb network activity thus offering additional targets for therapeutic intervention.
Learn More >Prolonged exposure to opioids results in analgesic tolerance, drug overdose, and death. The mechanism underlying morphine analgesic tolerance still remains unresolved. We show that morphine analgesic tolerance was significantly attenuated in germfree (GF) and in pan-antibiotic-treated mice. Reconstitution of GF mice with naïve fecal microbiota reinstated morphine analgesic tolerance. We further demonstrated that tolerance was associated with microbial dysbiosis with selective depletion in and Probiotics, enriched with these bacterial communities, attenuated analgesic tolerance in morphine-treated mice. These results suggest that probiotic therapy during morphine administration may be a promising, safe, and inexpensive treatment to prolong morphine's efficacy and attenuate analgesic tolerance. We hypothesize a vicious cycle of chronic morphine tolerance: morphine-induced gut dysbiosis leads to gut barrier disruption and bacterial translocation, initiating local gut inflammation through TLR2/4 activation, resulting in the activation of proinflammatory cytokines, which drives morphine tolerance.
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