Pain
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Multiple sclerosis (MS) is a neurodegenerative autoimmune disease with many known structural and functional changes in the central nervous system. A well-recognized, but poorly understood, complication of MS is chronic pain. Little is known regarding the influence of sex on the development and maintenance of MS-related pain. ⋯ We propose that tactile hypersensitivity in female EAE mice may be more immune-driven, whereas pain in male mice with EAE may rely more heavily on neurodegenerative and plasticity-related mechanisms. Morphological and inflammatory differences in the spinal cord associated with pain early in EAE progression supports the idea of differentially regulated pain pathways between the sexes. Results from this study may indicate future sex-specific targets that are worth investigating for their functional role in pain circuitry.
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Accumulating evidence has demonstrated that the enhanced synaptic plasticity of nociceptive interneurons in the spinal dorsal horn is the basis of central sensitization in neuropathic pain. Our previous results demonstrated that sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase, alleviates neuropathic pain in type 2 diabetes mellitus rats. SIRT1 has also been reported to regulate synaptic plasticity in different brain neurons. ⋯ SIRT1-shRNA induced pain behavior and enhanced structural synaptic plasticity in normal rats and increased synapse-associated proteins levels in normal rats and spinal neurons. Intrathecal injection of AAV-Cre-EGFP into SIRT1 mice also induced pain behavior and enhanced synaptic plasticity of the spinal dorsal horn neurons. These results suggest that SIRT1 plays an important role in the progression of DNP by regulating synaptic plasticity of spinal dorsal horn neurons.
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Pain-related diseases are the top leading causes of life disability. Identifying brain regions involved in persistent neuronal changes will provide new insights for developing efficient chronic pain treatment. Here, we showed that anterior nucleus of paraventricular thalamus (PVA) plays an essential role in the development of mechanical hyperalgesia in neuropathic and inflammatory pain models in mice. ⋯ At the circuitry level, PVA received innervation from central nucleus of amygdala, a known pain-associated locus. As a result, activation of right central nucleus of amygdala with blue light was enough to induce persistent mechanical hyperalgesia. These findings support the idea that targeting PVA can be a potential therapeutic strategy for pain relief.
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Oxytocin reduces primary sensory afferent excitability and produces analgesia in part through a peripheral mechanism, yet its actions on physiologically characterized, mechanically sensitive afferents in normal and neuropathic conditions are unknown. We recorded intracellularly from L4 dorsal root ganglion neurons characterized as low-threshold mechanoreceptors (LTMRs) or high-threshold mechanoreceptors (HTMRs) in female rats 1 week after L5 partial spinal nerve injury or sham control (n = 24 rats/group) before, during, and after ganglionic perfusion with oxytocin, 1 nM. Nerve injury desensitized and hyperpolarized LTMRs (membrane potential [Em] was -63 ± 1.8 mV in sham vs -76 ± 1.4 mV in nerve injury; P < 0.001), and sensitized HTMRs without affecting Em. ⋯ Sensory afferent neurons immunopositive for the vasopressin 1a receptor were larger (34 ± 6.3 μm, range 16-57 μm) than immunonegative neurons (26 ± 3.4 μm, range 15-43 μm; P < 0.005). These data replicate findings that neuropathic injury desensitizes LTMRs while sensitizing HTMRs and show rapid and divergent oxytocin effects on these afferent subtypes towards normal, potentially rebalancing input to the central nervous system. Vasopressin 1a receptors are present on medium to large diameter afferent neurons and could represent oxytocin's target.