Mol Pain
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Somatostatin (SST) and some of its receptor subtypes have been implicated in pain signaling at the spinal level. In this study we have investigated the role of SST and its sst2A receptor (sst2A) in dorsal root ganglia (DRGs) and spinal cord. ⋯ The findings highlight a significant and complex role of the SST system in pain signaling. The fact that the sst2A system is found also in human DRGs and spinal cord, suggests that sst2A may represent a potential pharmacologic target for treatment of neuropathic pain.
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T-type calcium channels and cannabinoid receptors are known to play important roles in chronic pain, making them attractive therapeutic targets. We recently reported on the design, synthesis and analgesic properties of a novel T-type channel inhibitor (NMP-7), which also shows mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the analgesic effect of systemically delivered NMP-7 (intraperitoneal (i.p.) or intragstric (i.g.) routes) on mechanical hypersensitivity in inflammatory pain induced by Complete Freund's Adjuvant (CFA) and neuropathic pain induced by sciatic nerve injury. ⋯ Overall, our work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation. Thus, this study provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/T-type channel blockers.
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In the present study, we examined spinal glial cell activation as a central nervous system mechanism of widespread mechanical hyperalgesia in rats that experienced chronic post-cast pain (CPCP) 2 weeks after cast immobilization. Activated spinal microglia and astrocytes were investigated immunohistologically in lumbar and coccygeal spinal cord segments 1 day, 5 weeks, and 13 weeks following cast removal. ⋯ These findings suggest that activation of lumbar cord astrocytes is an important factor in widespread mechanical hyperalgesia in CPCP.
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ATP and P2X receptors play important roles in the modulation of trigeminal neuropathic pain, while the role of G protein-coupled P2Y₂ receptors and the underlying mechanisms are less clear. The threshold and frequency of action potentials, fast inactivating transient K+ channels (IA) are important regulators of membrane excitability in sensory neurons because of its vital role in the control of the spike onset. In this study, pain behavior tests, QT-RT-PCR, immunohistochemical staining, and patch-clamp recording, were used to investigate the role of P2Y₂ receptors in pain behaviour. ⋯ Our data suggest that inhibition of P2Y₂ receptors leads to down-regulation of ERK-mediated phosphorylation and increase of the expression of I(A)-related Kv channels in trigeminal ganglion neurons, which might contribute to the clinical treatment of trigeminal neuropathic pain.
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Calcitonin gene-related peptide-α (CGRPα) is a classic marker of peptidergic nociceptive neurons and is expressed in myelinated and unmyelinated dorsal root ganglia (DRG) neurons. Recently, we found that ablation of Cgrpα-expressing sensory neurons reduced noxious heat sensitivity and enhanced sensitivity to cold stimuli in mice. These studies suggested that the enhanced cold responses were due to disinhibition of spinal neurons that receive inputs from cold-sensing/TRPM8 primary afferents; although a direct role for TRPM8 was not examined at the time. ⋯ Our data indicate that the enhanced behavioral responses to cold stimuli in CGRPα sensory neuron-ablated mice are dependent on functional TRPM8, whereas the other sensory and thermoregulatory phenotypes caused by CGRPα sensory neuron ablation are independent of TRPM8.