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MS Monasky, AR Zinsmeister, CW Stevens and TL Yaksh
Laboratory of Neurosurgical Research, Mayo Clinic, Rochester, Minnesota.
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 alpha 2 agonist. Such concurrent administration of ST-91 resulted in highly significant leftward shifts in the effect of morphine on the hot plate (52.5 degrees 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)] = alpha o(t) + beta 1.log doseM + beta 2.log doseST + beta 12.log doseM.log doseST Estimates of the principal coefficients beta 1, beta 2 and beta 12 corresponding to the overall effect of morphine alone, ST-91 alone and the interaction between the two were calculated: beta 1, beta 2 and beta 12. A statistical test of the interaction coefficient revealed that beta 12 was significantly (p less than .001) different from zero, indicating the powerful synergy between IT ST-91 and morphine. Confirmation of the synergistic nature of spinal opioid alpha 2 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 mu and alpha 2 adrenergic receptor systems.
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