Noxious peripheral stimulation produces antinociception mediated via substance P and opioid mechanisms in the rat tail-flick test

Physiological experiments were run to examine the effects of noxious thermal stimulation of one hindpaw on the tail-flick reflex in the lightly anesthetized rat. Male Sprague-Dawley rats were anesthetized with an i.p. injection of a mixture of Na-pentobarbital (20 mg/kg) and chloral hydrate (120 mg/kg). After baseline readings were taken in the tail-flick test, either a non-noxious or a noxious stimulus was applied which consisted of immersion of one hindpaw in water at 40, 45, 50 or 55°C for 1.5 min. After immersion, tail-flick readings were taken at 3-min intervals for at least 16 min. Paw immersion in water at 55°C induced an antinociceptive response, consisting of an increase in the reaction time, at 0.5 min after immersion. Recovery to baseline levels occurred over the next 3–6 min. Immersion at lower temperatures provoked smaller antinociceptive responses, except at 40°C, where readings remained around the baseline values. The increase in reaction time in response to immersion at 55°C was attenuated or blocked by the novel, nonpeptide substance P (NK-1) receptor antagonist, CP-96,345, administered s.c. 30 or 60 min, respectively, prior to paw immersion. Similar injection of CP-96,344, the inactive stereoisomer, had no effect on the response, while another NK-1 receptor antagonist, CP-99,994, also attenuated the antinociceptive effect of the immersion. The increase in reaction time induced by immersion at 55°C was absent in animals treated neonatally with capsaicin. This nociceptive response was blocked by the broad spectrum opiate antagonist, naloxone (10 mg/kg i.p.) given 20 min before paw immersion. The data provide evidence that a noxious stimulus produces an intensity-related heterosegmental antinociceptive effect and that C-fibers, and NK-1 and opiate receptors are involved in mediating this effect.