Mol 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.
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Various pathological conditions such as inflammation or injury can evoke pain hypersensitivity. That represents the response to innocuous stimuli or exaggerated response to noxious stimuli. The molecular mechanism based on the pain hypersensitivity is associated with changes in many of ion channels in dorsal-root ganglion (DRG) neurons. Anoctamin 1 (ANO1/TMEM16A), a Ca2+ activated chloride channel is highly visible in small DRG neurons and responds to heat. Mice with an abolished function of ANO1 in DRG neurons demonstrated attenuated pain-like behaviors when exposed to noxious heat, suggesting a role in acute thermal nociception. In this study, we further examined the function of ANO1 in mediating inflammation- or injury-induced hyperalgesia or allodynia. ⋯ In addition to ANO1's role in mediating acute thermal pain as a heat sensor, ANO1 is also capable of augmenting the excitability of DRG neurons under inflammatory or neuropathic conditions and thereby aggravates inflammation- or tissue injury-induced pathological pain.
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Bone cancer pain is currently a major clinical challenge for the management of cancer patients, and the cellular and molecular mechanisms underlying the spinal sensitization remain unclear. While several studies demonstrated the critical role of proteinase-activated receptor (PAR2) in the pathogenesis of several types of inflammatory or neuropathic pain, the involvement of spinal PAR2 and the pertinent signaling in the central sensitization is not determined yet in the rodent model of bone cancer pain. ⋯ The present study demonstrated that activation of PAR2 triggered NF-κB signaling and significantly upregulated the BDNF function, which critically contributed to the enhancement of glutamatergic transmission in spinal dorsal horn and thermal and mechanical hypersensitivity in the rats with bone cancer. This indicated that PAR2 - NF-κB signaling might become a novel target for the treatment of pain in patients with bone cancer.
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Substance P modulates ion channels and the excitability of sensory neurons in pain pathways. Within the heterogeneous population of Dorsal Root Ganglia (DRG) primary sensory neurons, the properties of cells that are sensitive to Substance P are poorly characterized. To define this population better, dissociated rat DRG neurons were tested for their responsiveness to capsaicin, ATP and acid. Responses to ATP were classified according to the kinetics of current activation and desensitization. The same cells were then tested for modulation of action potential firing by Substance P. ⋯ We conclude that excitatory effects of Substance P are restricted to a specific neuronal subpopulation with limited expression of putative nociceptive markers.
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The insular cortex (IC) is an important forebrain structure involved in pain perception and taste memory formation. Using a 64-channel multi-electrode array system, we recently identified and characterized two major forms of synaptic plasticity in the adult mouse IC: long-term potentiation (LTP) and long-term depression (LTD). ⋯ The impaired insular LTD could be pharmacologically rescued by priming the IC slices with a lower dose of DHPG application, a form of metaplasticity which involves activation of protein kinase C but not protein kinase A or calcium/calmodulin-dependent protein kinase II. These findings provide important insights into the synaptic mechanisms of cortical changes after peripheral amputation and suggest that restoration of insular LTD may represent a novel therapeutic strategy against the synaptic dysfunctions underlying the pathophysiology of phantom pain.