Nociceptors are specialized high-threshold sensory afferents from dorsal root ganglion (DRG) or other primary sensory (e.g., trigeminal) neurons that innervate the skin, muscle, joints, and viscera and respond to noxious or potentially damaging stimuli. Nociceptors express a unique repertoire of voltage-gated sodium (Na+) channels (Nav), potassium (K+) and calcium (Ca2+) channels, as well as cation channels of the transient receptor potential (TRP), acid-sensing ion channel (ASIC), and purinergic P2X families. These channels are responsible for the basic properties of nociceptors, including the lack of spontaneous activity and high threshold of activation. Products of inflammation or axonal injury trigger changes in the expression and function of these channels, resulting in increased excitability (reduced threshold of activation) of nociceptors. This process, known as peripheral nociceptor sensitization, manifests with spontaneous nociceptor activity (resulting in spontaneous pain), increased responsiveness and size of receptor fields for noxious stimulation (primary and secondary hyperalgesia), and nociceptor responses to innocuous mechanical or thermal stimuli (allodynia). These features characterize neuropathic and inflammatory pain. The wide variety of chemical signals that elicit nociceptor sensitization act via several types of receptors expressed in nociceptors, including G-protein-coupled receptors and tyrosine kinase receptors, which affect the expression or sensitivity of cation channels, particularly Nav1.7, Nav1.8, Nav1.9, TRP vanilloid 1 (TRPV1), and TRP ankyrin 1 (TRPA1) channels. Gain-of-function mutations affecting these channels are linked to familial syndromes characterized by episodic pain sporadic painful small fiber neuropathies (SFN); loss-of function mutations are associated with congenital insensitivity to pain. There are extensive and excellent reviews on all these subjects.
Neurology 2015
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