Mol Pain
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Primary sensory neurons in the dorsal root ganglia and trigeminal ganglia are responsible for sensing mechanical and thermal stimuli, as well as detecting tissue damage. These neurons express ion channels that respond to thermal, mechanical, or chemical cues, conduct action potentials, and mediate transmitter release. These neurons also express a large number of G-protein coupled receptors, which are major transducers for extracellular signaling molecules, and their activation usually modulates the primary transduction pathways. ⋯ On the other hand, receptors that couple to Gi/o proteins, such as opioid or GABAB receptors, are generally inhibitory. Their activation counteracts the effect of Gs-stimulation by inhibiting adenylate cyclase, as well as exerts effects on ion channels, usually resulting in decreased excitability. This review will summarize knowledge on Gi-coupled receptors in sensory neurons, focusing on their roles in ion channel regulation and discuss their potential as targets for analgesic and antipruritic medications.
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Complex regional pain syndrome is an extremely painful condition that develops after trauma to a limb. Complex regional pain syndrome exhibits autoimmune features in part mediated by autoantibodies against muscarinic-2 acetylcholine (M2) receptor. ⋯ As both complex regional pain syndrome and the proalgesic myelin basic protein activity are prevalent in females, this myelin basic protein/M2 homology presents an inviting hypothesis explaining the mechanisms of autoimmune pathogenesis and sexual dimorphism that underlies vulnerability toward developing complex regional pain syndrome and other pain states with neuropathic features. This hypothesis may aid in the development of novel diagnostic and therapeutic strategies to chronic pain.
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Voltage-gated sodium channel Nav1.7 is a threshold channel in peripheral dorsal root ganglion (DRG), trigeminal ganglion, and sympathetic ganglion neurons. Gain-of-function mutations in Nav1.7 have been shown to increase excitability in DRG neurons and have been linked to rare Mendelian and more common pain disorders. Discovery of Nav1.7 variants in patients with pain disorders may expand the spectrum of painful peripheral neuropathies associated with a well-defined molecular target, thereby providing a basis for more targeted approaches for treatment. ⋯ The patient responded to treatment with CBZ. Although CBZ did not depolarize activation of the mutant channel, it enhanced use-dependent inhibition. Our results demonstrate the presence of a novel gain-of-function variant of Nav1.7 in a patient with adult-onset painful peripheral neuropathy and the responsiveness of that patient to treatment with CBZ, which is likely due to the classical mechanism of use-dependent inhibition.
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Transient receptor potential vanilloid 1 (TRPV1) is a nonselective cation channel that is expressed in the sensory neurons and responds to various noxious stimuli including heat and capsaicin. The molecular properties of TRPV1 have been clearly examined; however, there are obvious individual differences in human sensitivity to thermal stimuli and capsaicin. ⋯ The sensitivities to burning pain and capsaicin of Japanese adult subjects were compared with their TRPV1 genome sequence, and we detected 6 single-nucleotide polymorphisms and 11 single-nucleotide polymorphisms related to burning pain and capsaicin sensitivity, respectively. In particular, homozygous I585V, a single-nucleotide polymorphism with amino acid substitution, significantly related to higher capsaicin sensitivity.
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Nociceptive signals originating in the periphery are conveyed to the brain through specific afferent and ascending pathways. The spino-(trigemino-)parabrachio-amygdaloid pathway is one of the principal pathways mediating signals from nociception-specific ascending neurons to the central amygdala, a limbic structure involved in aversive signal-associated emotional responses, including the emotional aspects of pain. Recent studies suggest that the right and left central amygdala play distinct roles in the regulation of nociceptive responses. ⋯ Although the single-sided formalin injection caused a significant bilateral increase in c-Fos-expressing neurons in the lateral parabrachial nucleus with slight projection-side dependence, the increase in the amplitude of postsynaptic excitatory currents and the number of c-Fos-expressing neurons in the central amygdala occurred predominantly on the right side regardless of the side of the inflammation. Although there was no significant correlation in the number of c-Fos-expressing neurons between the lateral parabrachial nucleus and central amygdala in the formalin-injected animals, these numbers were significantly correlated between the basolateral amygdala and central amygdala. It is thus concluded that the lateral parabrachial nucleus-central amygdala synaptic potentiation reported in various pain models is not a simple Hebbian plasticity in which raised inputs from the lateral parabrachial nucleus cause lateral parabrachial nucleus-central amygdala potentiation but rather an integrative and adaptive response involving specific mechanisms in the right central amygdala.