HYPERALGESIC AGENTS INCREASE A TETRODOTOXIN-RESISTANT NA+ CURRENT IN NOCICEPTORS

Sensitization of primary afferent neurons underlies much of the pain a nd tenderness associated with tissue injury and inflammation, The incr ease in excitability is caused by chemical agents released at the site of injury, Because recent studies suggest that an increase in voltage -gated Na+ currents may underlie increases in neuronal excitability as sociated with injury, we have tested the hypothesis that a tetrodotoxi n-resistant voltage-gated Na+ current (TTX-R I-Na), selectively expres sed in a subpopulation of sensory neurons with properties of nocicepto rs, is a target for hyperalgesic agents, Our results indicate that thr ee agents that produce tenderness or hyperalgesia in vivo, prostagland in E(2), adenosine, and serotonin, modulate TTX-R I-Na. These agents i ncrease the magnitude of the current, shift its conductance-voltage re lationship in a hyperpolarized direction, and increase its rate of act ivation and inactivation, In contrast, thromboxane B-2, a cyclooxygena se product that does not produce hyperalgesia, did not affect TTX-R I- Na. These results suggest that modulation of TTX-R I-Na is a mechanism for sensitization of mammalian nociceptors.