CHOLECYSTOKININ-B RECEPTOR ANTAGONISM ENHANCES THE ABILITY OF A LOW-DOSE OF MORPHINE TO REDUCE C-FOS EXPRESSION IN THE SPINAL-CORD OF THE RAT

Three hours after intraplantar carrageenin (6 mg/150 mu l) Fos-like im munoreactivity was predominantly observed in the superficial and deep laminae of the L4-L5 segments of the dorsal horn of the spinal cord in the rat. The total number of Fos-like immunoreactive neurons was equa lly divided between the superficial (laminae I-II) and deep laminae (l aminae V-VI), 99 +/- 3 and 102 +/- 7 Fos-like immunoreactive neurons p er section, respectively. In the absence of carrageenin stimulation a negligible number of Fos-like immunoreactive neurons were observed. Pr e-administered systemic morphine (0.3 mg/kg) did not significantly inf luence the total number of Fos-like immunoreactive neurons 3 h after c arrageenin. However, pre-administration of a higher dose of morphine ( 3 mg/kg) significantly reduced the total number of Fos-like immunoreac tive neurons (28 +/- 8% reduction, P < 0.001, as compared with control carrageenin Fos-like immunoreactive expression), with this effect bei ng equally divided between the superficial and deep laminae (29 +/- 5 and 29 +/- 6% reduction, respectively, P < 0.001, as compared with con trol carrageenin Fos-like immunoreactive expression, for both). Pre-ad ministration of the selective cholecystokinin B receptor antagonist, L -365-260 (0.2 mg/kg), alone did not influence the total number of Fos- like immunoreactive neurons 3 h after carrageenin. Co-administration o f the ineffective dose of morphine (0.3 mg/kg) and the ineffective dos e of L-365-260 (0.2 mg/kg) significantly reduced the total number of F os-like immunoreactive neurons (23 +/- 5% reduction, P < 0.05, as comp ared with control carrageenin Fos-like immunoreactive expression), wit h this effect being equally divided between the superficial and deep l aminae (22 +/- 4 and 27 +/- 5% reduction, respectively, P < 0.05, as c ompared with control carrageenin Fos-like, immunoreactive expression, for both). The effect of co-administered morphine (0.3 mg/kg) and L-36 5-260 on the total number of Fos-like immunoreactive neurons was signi ficantly different from the lack of effect of the same dose of morphin e alone (P < 0.05) and the same dose of L-365-260 alone (P < 0.05), bu t was not significantly different from the effect of 3 mg/kg of morphi ne alone. Pre-administration of morphine (3 mg/kg) and L-365-260 (0.2 mg/kg) significantly reduced the total number of Fos-like immunoreacti ve neurons (34 +/- 5% reduction, P < 0.001, as compared with control c arrageenin Fos-like immunoreactive expression), but was not significan tly different from the effect of 3 mg/kg of morphine alone. Our result s provide evidence that a normally ineffective dose of morphine admini stered with the cholecystokinin B receptor antagonist, L-365-260, redu ces spinal Fos expression associated with prolonged pain processing. H owever, as illustrated by the lack of interaction between the high dos e of morphine and L-365-260, the relationship between the opioids and anti-opioid peptides are not fixed and ubiquitous for all doses of mor phine.