Abstract
BackgroundSystemically 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.ResultsWhole-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 peripherin-positive small-diameter DRG neurons, and some of them were α2A-AR-positive ones. Our electrophysiological recordings also demonstrated that DEX-induced inhibition of Nav1.8 currents was prevented by intracellular application of G-protein inhibitor GDPβ-s or Gi/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 Nav1.8 currents.ConclusionsWe established a functional link between α2-AR and Nav1.8 in primary sensory neurons utilizing the Gi/o/AC/cAMP/PKA pathway, which probably mediating peripheral analgesia of DEX.
Highlights
Administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation
We investigated whether the peripheral DEX-induced analgesia might in part arise from the suppressed activation of TTX-R sodium channel Nav1.8 currents via binding to its G-protein-coupled receptors (GPCRs) α2-ARs in small-diameter dorsal root ganglion (DRG) neurons
In this study, we demonstrated that selective α2-AR agonist dexmedetomidine (DEX) reduced Nav1.8 currents in small-diameter acutely dissociated DRG neurons
Summary
Administered dexmedetomidine (DEX), a selective α2 adrenergic receptor (α2-AR) agonists, produces analgesia and sedation. Tetrodotoxinresistant (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. Dexmedetomidine (DEX), a potent and highly selective agonist of the alpha 2 adrenergic receptors (α2-ARs) with more favorable pharmacokinetic properties than clonidine (another commonly used α2-AR agonist) is approved for the adult intensive care unit use as sedative infusion by the US Food and Drug Administration in 1999. Administered α2-AR agonists produce anti-nociceptive effects in humans and animals, suggesting that the α2-AR may be involved in anti-nociception at the supraspinal, spinal and peripheral levels [6,7,8,9]. 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 [7]
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