A study of the antinociceptive interaction between intrathecal opioids and α-adrenergic agonists in the spinal cord of the rat

Abstract

The role and mechanism of action of α₁-adrenoceptors in adrenergic spinal antinociception is uncertain. α₁-Adrenoceptors are normally excitatory in the CNS, suggesting that any inhibitory effect on nociception must be indirect. Recently, we showed that intrathecal (i.t.) α₁-agonists potentiate α₂-induced spinal antinociception in the rat by a δ-receptor mediated, enkephalin-dependent process. If enkephalins, released from spinal interneurons, mediate the antinociceptive effect of α₁-adrenoceptors, then non-selective α-agonists (i.e. norepinephrine; NE) should exhibit cross-tolerance to δ-agonists (i.e. DADLE), but not to μ-agonists (i.e. morphine), in the spinal cord. Conversely, the antinociceptive effect of α₂-selective agonists (i.e, dexmedetomidine; DX) should be unaffected by spinal opioid tolerance. To test these hypotheses, male, Sprague-Dawley rats (300-400g) were continuously infused with i.t. saline (1 μl/h), morphine (MOR; 5, 10, or 20 μg/h) or DADLE (10 μg/h) for 6 days using ALZET osmotic mini-pumps. Antinociception was assessed using the tail flick (TF) test. In an initial time course study, significant recovery from DADLE and MOR tolerance did not occur until day 3 and 4 post-infusion (PI), respectively. In subsequent cross-tolerance experiments, NE and DX dose-response curves were determined on days 1 and 2 PI for DADLE-pretreated rats, and on days 1-3 PI in MOR-pretreated rats. The table of ED₅₀ ratios for i.t. NE and DX in opioid- and saline-infused animals demonstrates that NE exhibits significant (*) cross-tolerance to DADLE, but not morphine. No cross-tolerance was observed between DX and DADLE. -- [table in abstract is omitted] -- In separate groups of rats, i.p. naloxone significantly attenuated the antinociceptive effect of MOR, but not DADLE, on day 1 of infusion (time of peak antinociception); i.p. naltrindole significantly antagonized DADLE, but not MOR. These data indicate that μ- and δ-receptor selectivity was retained during infusion, consistent with the different cross-tolerance results to NE. The marked antagonism of i.t. DX by Wyeth 27127, but not by prazosin, confirmed the α₂-selectivity of DX at the doses used. The results of this study are consistent with the hypothesis that α₁-adrenoceptors facilitate the release of enkephalins in the spinal cord which, in turn, effect antinociception by a δ-receptor mechanism.