WHEN IS THE MAXIMAL EFFECT OF PRE-ADMINISTERED SYSTEMIC MORPHINE ON CARRAGEENAN EVOKED SPINAL C-FOS EXPRESSION IN THE RAT

This study evaluated, in awake rats, the time course of the expression of c-Fos in spinal cord neurons, in the IA-LS segments, at various ti me points after intraplantar carrageenin (0.5 h, 1 h, 1.5 h, 2 h and 2 .5 h). In addition, the effects of pre-administered morphine (3 mg/kg, i.v.) on the c-Fos expression, at the various time points, were studi ed. Very few Fos-like immunoreactive (Fos-LI) neurons were observed 0. 5 h after carrageenin. However, spinal c-Fos expression increased init ially (at 1 h), in the superficial laminae (I-II) of the spinal dorsal horn, and incrementally increased both in the superficial and deep (V -VI) laminae at later time points after carrageenin. Systemic morphine did not significantly decrease the number of superficial Fos-LI neuro ns observed 1 h after carrageenin, whereas it significantly reduced th e number of superficial Fos-LI neurons induced at 1.5 h and 2 h after carrageenin (58 +/- 3% and 57 +/- 10% reduction, P < 0.001, respective ly). In addition, morphine reduced the number of deep Fos-LI neurons a t 1.5 h and 2 h after carrageenin (86 +/- 4%, P < 0.01 and 82 +/- 8%, P < 0.001 reduction as compared to control carrageenin expression, res pectively). In contrast, morphine was less efficacious in decreasing t he number of Fos-LI neurons observed in the superficial and deep lamin ae at 2.5 h after carrageenin (34 +/- 6% and 59 +/- 6% reduction, P < 0.001, respectively). Thus, the peak effect of pre-administered morphi ne on carrageenin evoked c-Fos expression was observed 1.5 h and 2 h a fter intraplantar carrageenin, with a weaker effect observed at 2.5 h after carrageenin. The pharmacokinetic complications between the time course of the antinociceptive effects of morphine and c-Fos expression is discussed. These results clearly demonstrate that studies of c-Fos expression with pharmacological investigations should take into consi deration this finding since one delay after the stimulation does not g ive a full indication of the full potential of the drug tested.