Antinociceptive interactions between alpha 2-adrenergic and opiate agonists at the spinal level in rodents

This study was undertaken to evaluate the antinociceptive interactions of alpha 2 adrenergic and opiate receptors at the spinal level. Morphine and clonidine were administered intrathecally (i.t.) by lumbar puncture to rats either alone or in the presence of either i.t. yohimbine, an alpha 2 antagonist, or systemic naloxone, an opioid antagonist. The effect of tolerance to systematically administered morphine on responses to i.t. morphine and clonidine was examined in mice. Antinociception was determined by observing the response to a clamp applied to the tail (Haffner test) in mice and by the tail-flick test in rats; log dose-response curves for antinociception were generated for morphine, clonidine, and each drug combination. Morphine and clonidine both produced dose-dependent antinociception when given i.t. in both species. The i.t. administration of yohimbine attenuated the antinociceptive effect of both clonidine and morphine, but naloxone attenuated only the response to morphine. Further, a sub-analgetic dose of i.t. clonidine potentiated the effect of i.t. morphine. In morphine-tolerant mice, i.t. morphine was not efficacious whereas clonidine retained full efficacy, although potency was slightly diminished. Thus, it appears that alpha 2 adrenoceptor-mediated antinociception is independent of opiate receptor mechanisms. Clinical use of intrathecal combinations of alpha 2 adrenergic and opiate receptor agonists to increase analgesia and use of intrathecal alpha 2 agonists for pain relief in patients tolerant to opiates might deserve evaluation.