Trichloroethanol, an Active Metabolite of Chloral Hydrate, Modulates Tetrodotoxin-resistant Na Channels in Rat Nociceptive Neurons

Background: Chloral hydrate is a sedative-hypnotic drug widely used for relieving fear and anxiety in pediatric patients. However, mechanisms underlying the chloral hydrate-mediated analgesic action remain unexplored. Therefore, we investigated the effect of 2',2',2'-trichloroethanol (TCE), the active metabolite of chloral hydrate, on tetrodotoxin-resistant (TTX-R) Na channels expressed in nociceptive sensory neurons.

Methods: The TTX-R Na current (I) was recorded from acutely isolated rat trigeminal ganglion neurons using the whole-cell patch-clamp technique.

Results: Trichloroethanol decreased the peak amplitude of transient TTX-R I in a concentration-dependent manner and potently inhibited persistent components of transient TTX-R I and slow voltage-ramp-induced I at clinically relevant concentrations. Trichloroethanol exerted multiple effects on various properties of TTX-R Na channels; it (1) induced a hyperpolarizing shift on the steady-state fast inactivation relationship, (2) increased use-dependent inhibition, (3) accelerated the onset of inactivation, and (4) retarded the recovery of inactivated TTX-R Na channels. Under current-clamp conditions, TCE increased the threshold for the generation of action potentials, as well as decreased the number of action potentials elicited by depolarizing current stimuli.

Conclusions: Our findings suggest that chloral hydrate, through its active metabolite TCE, inhibits TTX-R I and modulates various properties of these channels, resulting in the decreased excitability of nociceptive neurons. These pharmacological characteristics provide novel insights into the analgesic efficacy exerted by chloral hydrate.