Multiplicative interaction between narcotic agonisms expressed at spinal and supraspinal sites of antinociceptive action as revealed by concurrent intrathecal and intracerebroventricular injections of morphine.

In rats in which the fourth ventricular exits had been acutely occluded, morphine sulfate was injected concomitantly into the spinal subarachnoid space (0-10 micrograms/4 microliter) and into the third cerebral ventricle (0-50 micrograms/5 microliter). The combinations of intrathecal (i.t.) and intracerebroventricular (i.v.t.) dosages used were selected to yield particular ratios of supraspinal to spinal (SS:S) agonisms. Dose-response lines for both the tail-flick and hot plate responses were constructed for each SS:S ratio, with the abscissa representing i.v.t. morphine dosage. It was observed that the analgetic potency of morphine injected i.v.t. was profoundly potentiated by the concurrent administration of morphine i.t. Dose-response lines for i.v.t. morphine were shifted progressively to the left as the spinal dose of morphine was increased. At the optimal balance of spinal and supraspinal dosage (SS:S = 1:1), the ED50 values for i.v.t. morphine for the hot plate and tail-flick tests were reduced by factors of 45 and 29, respectively. A similar, but less profound, potentiation of the analgetic potency of morphine injected i.t. by concurrent administration of morphine i.v.t. was observed. Isobolographic analysis of the data revealed that the isobols were hyperbolas having extreme negative curvature of all effect levels. Inspection of the isobols indicated that, at all ratios of spinal to supraspinal agonism which could conceivably be obtained when morphine is given systemically, the spinal-supraspinal interaction is multiplicative. The results suggest that narcotic agonism at both spinal and supraspinal narcotic-sensitive sites is essential to the production of analgesia by systemically administered morphine and that neither site can logically be deemed the "primary" site of narcotic action.