Hyperalgesic agents increase a tetrodotoxin-resistant Na+ current in nociceptors.

TLDR

Sensitization of primary afferent neurons underlies pain and tenderness from tissue injury and inflammation, driven by chemical agents released at the injury site. The study tests whether the tetrodotoxin‑resistant voltage‑gated Na⁺ current (TTX‑R INa) is a target for hyperalgesic agents. The authors examined this by measuring TTX‑R INa responses to hyperalgesic agents in nociceptor‑like sensory neurons. Prostaglandin E₂, adenosine, and serotonin increased TTX‑R INa magnitude, shifted its conductance‑voltage relationship hyperpolarized, and accelerated activation and inactivation, whereas thromboxane B₂ had no effect, indicating that TTX‑R INa modulation underlies nociceptor sensitization.

Abstract

Sensitization of primary afferent neurons underlies much of the pain and tenderness associated with tissue injury and inflammation. The increase 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 associated with injury, we have tested the hypothesis that a tetrodotoxin-resistant voltage-gated Na+ current (TTX-R INa), selectively expressed in a subpopulation of sensory neurons with properties of nociceptors, is a target for hyperalgesic agents. Our results indicate that three agents that produce tenderness or hyperalgesia in vivo, prostaglandin E2, adenosine, and serotonin, modulate TTX-R INa. These agents increase the magnitude of the current, shift its conductance-voltage relationship in a hyperpolarized direction, and increase its rate of activation and inactivation. In contrast, thromboxane B2, a cyclooxygenase product that does not produce hyperalgesia, did not affect TTX-R INa. These results suggest that modulation of TTX-R INa is a mechanism for sensitization of mammalian nociceptors.