Voltage-gated Na+ channels, composed of one pore-forming (-subunit and one or more auxiliary p-subunits, are crucial for neuronal excitability and propagation of action potentials (178,179). Among the 10 known a-subunits are two tetrodotoxin-resistant Na+ channels, Nav1.8 (previously termed SNS/PN3) and Nav1.9 (SNS2/NaN) and one tetrodotoxin-sensitive Na+ channel, Nav1.7 (PN1), that are preferentially expressed by nociceptive DRG neurons (178182). Tetrodotoxin-resistant Na+ currents are also present in vagal and spinal afferent neurons supplying the rat stomach (183) and in DRG neurons projecting to the rat ileum and colon (127,184-186). There is mounting evidence that tetrodotoxin-resistant Na+ channels play a role in neuropathic and inflammatory hyperalgesia (178,179). Experimental gastritis and trinitroben-zene sulphonic acid (TNBSA)-induced ileitis enhance the excitability of DRG neurons predominantly via an increase of Nav1.8 currents (183,186,187). Similar alterations in vagal afferents are seen in rats with acetic acid-induced gastric ulcers (188). The upregulation of tetrodotoxin-resis-tant Na+ currents in DRG neurons following GI inflammation and injury involves nerve growth factor and proinflammatory mediators such as PGE2 (184,189,190).
Antisense probe-induced inhibition of Nav1.8 expression in rat spinal afferents prevents the effect of intravesical acetic acid to induce urinary bladder hyperalgesia (191). Null mutation of the Nav1.8 gene does not alter behavioral pain responses to acute noxious stimulation of abdominal viscera, but attenuates the behavioral reactions to colonic sensitization by capsaicin or mustard oil and prevents referred hyperalgesia (192). It would seem, therefore, that tetrodotoxin-resistant Na+ channels, particularly Nav1.8, constitute a new target for the treatment of visceral hyperalgesia due to inflammation. While selective blockers for tetrodotoxin-resistant Na+ channels have not yet been disclosed, nonselective inhibitors of voltage-gated Na+ channels such as lidocaine (193,194), mexiletine, and carbamazepine (195) suppress the central signaling of colonic distension by spinal afferents. It has been suggested that the analgesic effect of the antidepressant drug amitryptiline may also arise from a use-dependent block of voltage-dependent Na+ channels on sensory neurons (196).
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