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

Bautista, John Cruz (1996) A study of the antinociceptive interaction between intrathecal opioids and α-adrenergic agonists in the spinal cord of the rat. Masters thesis, Memorial University of Newfoundland.

[English] PDF (Migrated (PDF/A Conversion) from original format: (application/pdf)) - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. Download (14MB) [English] PDF - Accepted Version Available under License - The author retains copyright ownership and moral rights in this thesis. Neither the thesis nor substantial extracts from it may be printed or otherwise reproduced without the author's permission. (Original Version)

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.

Actions (login required)

View Item