Dexmedetomidine inhibits Tetrodotoxin-resistant Na(v)1.8 sodium channel activity through G(i/o)-dependent pathway in rat dorsal root ganglion neurons

BACKGROUND: 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 Na(v)1.8 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 Na(v)1.8 currents in acutely dissociated small-diameter DRG neurons. RESULTS: Whole-cell patch-clamp recordings demonstrated that DEX concentration-dependently suppressed TTX-R Na(v)1.8 currents in small-diameter lumbar DRG neurons. DEX also shifted the steady-state inactivation curves of Na(v)1.8 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 α2(A)-AR antagonist BRL44408 but not α2(B)-AR antagonist imiloxan blocked the inhibition of Na(v)1.8 currents by DEX. Immunohistochemistry results showed that Na(v)1.8 was predominantly expressed in peripherin-positive small-diameter DRG neurons, and some of them were α2(A)-AR-positive ones. Our electrophysiological recordings also demonstrated that DEX-induced inhibition of Na(v)1.8 currents was prevented by intracellular application of G-protein inhibitor GDPβ-s or G(i/o) proteins inhibitor pertussis toxin (PTX), and bath application of adenylate cyclase (AC) activator forskolin or membrane-permeable cAMP analogue 8-Bromo-cAMP (8-Br-cAMP). PKA inhibitor Rp-cAMP could mimic DEX-induced inhibition of Na(v)1.8 currents. CONCLUSIONS: We established a functional link between α2-AR and Na(v)1.8 in primary sensory neurons utilizing the G(i/o)/AC/cAMP/PKA pathway, which probably mediating peripheral analgesia of DEX.