Attenuation of morphine tolerance after antisense oligonucleotide knock‐down of spinal mGluR1

Abstract

1 Chronic systemic treatment of rats with morphine leads to the development of opioid tolerance. This study was designed to examine the e ects of intrathecal (i.t.) infusion of a metabotropic glutamate receptor 1 (mGluR1) antisense oligonucleotide, concomitant with chronic morphine treatment, on the development of tolerance to morphine's antinociceptive e ects. 2 All rats received chronic (6 day) s.c. administration of morphine to induce opioid tolerance. Additionally, rats were treated with either mGluR1 antisense (AS), missense (MIS) or arti®cial cerebrospinal¯uid (ACSF) by i.t. infusion via chronically implanted i.t. catheters connected to osmotic mini-pumps. The e ects of acute i.t. or s.c. morphine on tail-¯ick latencies were assessed prior to and following chronic s.c. morphine treatment for all chronic i.t. infusion groups. mGluR1 protein level in the spinal cord was determined by Western blot analysis for all treatments, assessing the e ciency of knock-down with AS treatment. 3 Acute i.t. morphine dose-dependently produced antinociception in the tail-¯ick test in naõÈ ve rats. Systemic morphine-treated rats administered i.t. ACSF or MIS developed tolerance to i.t. morphine. Chronic i.t. infusion with mGluR1 AS signi®cantly reduced the development of tolerance to i.t. morphine. 4 In contrast to i.t. morphine, tolerance developed to the antinociceptive e ects of s.c. morphine, in all i.t. infusion groups, including the mGluR1 AS group. 5 The spinal mGluR1 protein level was dramatically decreased after mGluR1 AS infusion when compared to control animals (naõÈ ve and ACSF-treated animals). 6 These ®ndings suggest that the spinal mGluR1 is involved in the development of tolerance to the antinociceptive e ects of morphine. Selective blockade of mGluR1 may be bene®cial in preventing the development of opioid analgesic tolerance.

Pharmacological characterization of the bifunctional opioid ligand H-Dmt-Tic-Gly-NH-Bzl (UFP-505) †

“…Additionally, in the same study, a similar tolerance-deficit profile to morphine has been shown in N-methyl-D-aspartate receptor-deficient mice, underlying the possibility that common mechanisms of the development of morphine tolerance also exist between opioid and non-opioid receptors. These interesting interactions have also been confirmed in a different study by Sharif and colleagues 8 where intrathecal administration of metabotropic glutamate receptor-1 antisense oligonucleotides in rats resulted in an attenuation of morphine tolerance. Finally, based on studies that have shown a reduction in the development of tolerance to morphine by NOP receptor blockade or in NOP receptor knockouts, the co-administration of a MOP agonist and NOP antagonist has been proposed.…”

Metabotropic Glutamate 1 Receptor: Current Concepts and Perspectives

“…It is noteworthy that the use of mGlu1 antisense oligonucleotides also revealed a role for mGlu1 in the development of tolerance to morphine, as the analgesic response to morphine is conserved in antisense-treated neuropathic animals (Fundytus et al, 2001;Sharif et al, 2002).…”

mGluR5 antagonists that block calcium mobilization in vitro also reverse (S)-3,5-DHPG-induced hyperalgesia and morphine antinociceptive tolerance in vivo

“…This led to the hypothesis that group I mGlu receptor antagonists would reverse antinociceptive tolerance. Sharif et al (2002) demonstrated that i.t. infusion of antisense oligonucleotide to the mGluR1 during 6 days of s.c. morphine administration prevented the development of morphine tolerance.…”