Development of tolerance to the antinociceptive effect of systemic morphine at the lumbar spinal cord level: a c-Fos study in the rat

The development of tolerance to the antinociceptive effects of morphine was investigated in rats using carrageenin-induced spinal c-Fos expression. We took advantage of this technique to especially study, at the cellular leve l, in freely moving animals, the development of tolerance based on the visu alization of dorsal horn spinal cord neurons which play a major role in noc iceptive processes. Two hours after intraplantar injection of carrageenin ( 6 mg/150 mu l of saline), c-Fos-like immunoreactivity (FLI) was observed pr edominantly in the superficial and deep laminae of the dorsal horn in segme nts L4 and L5 of the spinal cord. In naive rats, acute intravenous morphine (3 mg/kg, i.v.) reduced the number of superficial and deep FLI neurons; 49 % and 59% reduction respectively (p < 0.0001 for both). In morphine-pretrea ted rats (daily administration of subcutaneous morphine: 1, 3, 5, 10, 20 or 40 mg/kg once a day for 4 days), antinociceptive tolerance tested on day 5 by acute morphine (3 mg/kg, i.v.) was manifest in those groups pretreated with the highest doses of morphine (10, 20 or 40 mg/kg). From regression an alysis, it appeared that tolerance to the antinociceptive effect of morphin e developed progressively as a function of the chronic morphine dose used o n neurons involved in spinal nociceptive processes (superficial and deep do rsal horn neurons). Similarly, in rats pretreated with 10 mg/kg of morphine over 1, 2, 3 or 4 days, tolerance progressively developed, for both spinal neuronal populations, as a function of the duration of the pretreatment. T hese results are discussed in the context of the several possible sites of action of morphine. (C) 1998 Published by Elsevier Science B.V. All rights reserved.