Interaction of intrathecal morphine and ST-91 on antinociception in the rat: Dose-response analysis, antagonism and clearance

Physiological data suggest that the direct effect of spinal opiates as well as the activation of adrenergic bulbospinal pathways each results in a reduction in the gain of the stimulus response function in dorsal horn neurons. In its simplest form, this suggests the hypothesis that co-activation of spinal alpha₂ and opioid receptors should be manifested as a synergistic interaction in which in its simplest form the net effect would be a product of the effect produced by either drug alone. To assess this hypothesis, rats were prepared with chronically implanted intrathecal (IT) catheters. Dose-response curves for IT morphine were obtained in the presence of fixed doses (0.01 nmol, 0.03 nmol, 0.1 nmol, 0.3 nmol) of 2-[2,6-dimethylphenylamino]-2-imidazoline (ST-91), an alpha₂ agonist. Such concurrent administration of ST-91 resulted in highly significant leftward shifts in the effect of morphine on the hot plate (52.5°C) measure with a significant increase in dose-response curve slopes. To minimize the effects of the cut-off time necessary in an antinociceptive measure, a 'Cox proportional hazard' analysis was used. The (log) Hazard function log[h(t)] is expressed as a linear function of the effects resulting from the action of morphine, the action of ST-91 and as a function of an interaction of morphine and ST-91, e.g., the general form is: log[h(t)] = α₀(t) + β₁ · log dose(M) + β₂ · log dose(ST)(+ β₁₂ · log dose(M) · log dose(ST)). Estimates of the principal coefficients β₁, β₂ and β₁₂ corresponding to the overall effect of morphine alone, ST-91 alone and the interaction between the two were calculated: β₁, β₂ and β₁₂. A statistical test of the interaction coefficient revealed that β₁₂ was significantly (p < .001) different from zero, indicating the powerful synergy between IT ST-91 and morphine. Confirmation of the synergistic nature of spinal opioid alpha₂ receptors was provided by the fact that IT injection of naloxone (90 nmol) or phentolamine (100 nmol) after IT injection of various combinations of morphine and ST-91 immediately and completely abolished the potentiating effect of the combination. The clearance of IT [³H]morphine from the thoracic and lumbar spinal cord was not changed in the presence of ST-91. These observations suggest a potent synergistic interaction between spinal μ and alpha₂ adrenergic receptor systems.