Dexmedetomidine inhibits Tetrodotoxin-resistant Nav1.8 sodium channel activity through Gi/o-dependent pathway in rat dorsal root ganglion neurons
Abstract
Systemically administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation. Peripherally restricted α2-AR antagonist could block the analgesic effect of systemic DEX on neuropathic pain, with no effect on sedation, indicating peripheral analgesic effect of DEX. Tetrodotoxin-resistant (TTX-R) sodium channel Nav1.8 play important roles in the conduction of nociceptive sensation. Both α2-AR and Nav1.8 are found in small nociceptive DRG neurons. We, therefore, investigated the effects of DEX on the Nav1.8 currents in acutely dissociated small-diameter DRG neurons. Whole-cell patch-clamp recordings demonstrated that DEX concentration-dependently suppressed TTX-R Nav1.8 currents in small-diameter lumbar DRG neurons. DEX also shifted the steady-state inactivation curves of Nav1.8 in a hyperpolarizing direction and increased the threshold of action potential and decrease electrical and chemical stimuli-evoked firings in small-diameter DRG neurons. The α2-AR antagonist yohimbine or α2A-AR antagonist BRL44408 but not α2B-AR antagonist imiloxan blocked the inhibition of Nav1.8 currents by DEX. Immunohistochemistry results showed that Nav1.8 was predominantly expressed in peripheri...Continue Reading
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