MULTIPLICATIVE INTERACTION BETWEEN NARCOTIC AGONISMS EXPRESSED AT SPINAL AND SUPRASPINAL SITES OF ANTINOCICEPTIVE ACTION AS REVEALED BY CONCURRENT INTRATHECAL AND INTRACEREBROVENTRICULAR INJECTIONS OF MORPHINE

Abstract

In rats in which the 4th ventricular exits were acutely occluded, morphine sulfate was injected concomitantly into the spinal subarachnoid space (0-10 .mu.g/4 .mu.l) and into the 3rd cerebral ventricle (0-50 .mu.g/5 .mu.l). 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 the tail-flick and hot plate responses were constructed to each SS:S ratio, with the abscissa representing i.v.t. morphine dosage. 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. 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. Apparently narcotic agonism at spinal and supraspinal narcotic-sensitive sites is essential to the production of analgesia by systemically administered morphine and neither site can logically be deemed the primary site of narcotic action.