Behavioural tolerance to morphine analgesia is supraspinally mediated: a quantitative analysis of dose-response relationships

Repeated exposure of a rat to a nociceptive testing environment (‘habituation’) enhances its sensitivity to noxious thermal stimuli 20 and reduces the antinociceptive effect of a subsequent acute dose of morphine (‘behavioural tolerance’). The present study quantitatively characterises the effects of habituation upon morphine antinociception using hot-plate (50 and 55 °C) and reflex withdrawal tests (dipping the tail and hindpaws into water at 49 °C). Dose-response relationships were modeled with the empirical function; (E = E 0 + (E MAX*D N)/(ED 50 N + D N) where E is the time-integrated response, E MAX is the response attributable to morphine, E 0 is the baseline response, D is the dose and N is a steepness parameters. Habituation reduced E MAX in both hot-plate tests and also reduced E 0 on the 50 °C hot-plate. In both reflex tests, habituation reduced E 0 to that of spinal animals and E MAX to a value intermediate between that of intact and spinal animals. Neither the ED 50 nor the value of N was altered by habituation. Acute spinal novice and habituated animals had similar dose-response curves and parameters. Sham spinalisation had no significant effect on any of the parameters. It is concluded that habituation to the nociceptive testing environment substantially reduces the bulbospinal contribution to morphine analgesia but has no effect upon the spinal component.