Studies in the Primate on the Analgetic Effects Associated with Intrathecal Actions of Opiates,α-Adrenergic Agonists and Baclofen

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Abstract
The effects of intrathecally administered opiates (morphine sulfate and meperidine), .alpha.-adrenergic agonists (clonidine and ST-91 [2-(2,6-diethyl-phenylamino)-2-imidazoline]) and baclofen were examined on the shock titration threshold of macaque monkeys chronically prepared with intrathecal (I) or epidural (E) catheters. Spinal opiates produced a long-lasting analgesia which was antagonized by naloxone. The order of potency was I morphine > I meperidine > E meperidine > E morphine. Clonidine and ST-91 also produced a dose-dependent, long-lasting elevation in the shock titration threshold, antagonized by phentolamine but not naloxone. L-Baclofen, but not D-baclofen, resulted in a dose-dependent elevation of shock titration threshold, which was not antagonized by naloxone. Repeated administration at 24 h intervals over a 7 day period of morphine, clonidine or baclofen, resulted in a significant reduction in the analgestic effects of each drug. Cross tolerance between the 3 classes of agents was not observed. Intrathecal co-administration of inactive doses of ST-91 and morphine resulted in a near maximal increase in the shock titration threshold, which failed to show any significant tolerance over 21 days. Intrathecal ST-91 and morphine produced no change in either muscle strength, tendon reflexes, respiratory rate, urine formation or the ability to locomote. Baclofen produced a dose-dependent decrease in muscle strength. That the intrathecal drugs did not produce anesthesia was demonstrated by their failure to block the avoidance response to ensuing ear shock cued by a light tactile stimulus applied to the hind paw. A powerful analgesia can be produced by selectively activating adrenergic, opiate and baclofenergic receptor systems in the spinal cord.