Sites of antinociceptive action of systemically injected morphine: involvement of supraspinal loci as revealed by intracerebroventricular injection of naloxone.

Dose-response lines for the tail-flick and hot plate tests were obtained in rats which had received systemic injections of morphine (10-150 mg/kg i.p.) and intracerebroventricular (i.v.t.) injections of naloxone (3-20 micrograms). Diffusion studies indicated that the antagonist remained localized within supraspinal structures. Between the doses of 3 and 10 micrograms i.v.t. naloxone produced a dose-dependent rightward shifting of the morphine dose-response lines, the shift produced by the 10-micrograms dose being sufficient to abolish the analgetic action of morphine doses as large as 75 mg/kg. Higher doses of naloxone (e.g., 20 micrograms) produced no additional rightward shift, indicating an inability of i.v.t. naloxone to antagonize the analgesia produced by high systemic doses of morphine. These findings seem to suggest that analgesia produced by low to moderate systemic doses of morphine is mediated entirely by an action of the narcotic upon supraspinal structures. However, the results of an analogous study in which naloxone was injected into the spinal subarachnoid space indicated that analgesia produced by morphine given systemically in low to moderate doses is mediated exclusively by an action on the spinal cord. This apparent paradox can be resolved if one assumes that the total analgesia observed after a low to moderate systemic dose of morphine is a result of a multiplicative, rather than an additive, interaction of narcotic agonisms expressed at the spinal and supraspinal sites of action, respectively.