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Comparative Study
. 2002 Jul;136(6):865-72.
doi: 10.1038/sj.bjp.0704792.

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

Reza N Sharif  1 , Michael Osborne, Terence J Coderre, Marian E Fundytus
Affiliations
Comparative Study

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

Reza N Sharif et al. Br J Pharmacol. 2002 Jul.

Abstract

1. Chronic systemic treatment of rats with morphine leads to the development of opioid tolerance. This study was designed to examine the effects 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 effects. 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 artificial cerebrospinal fluid (ACSF) by i.t. infusion via chronically implanted i.t. catheters connected to osmotic mini-pumps. The effects of acute i.t. or s.c. morphine on tail-flick 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 efficiency of knock-down with AS treatment. 3. Acute i.t. morphine dose-dependently produced antinociception in the tail-flick test in naïve rats. Systemic morphine-treated rats administered i.t. ACSF or MIS developed tolerance to i.t. morphine. Chronic i.t. infusion with mGluR1 AS significantly reduced the development of tolerance to i.t. morphine. 4. In contrast to i.t. morphine, tolerance developed to the antinociceptive effects 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 (naïve and ACSF-treated animals). 6. These findings suggest that the spinal mGluR1 is involved in the development of tolerance to the antinociceptive effects of morphine. Selective blockade of mGluR1 may be beneficial in preventing the development of opioid analgesic tolerance.

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Figures

Figure 1
Figure 1
Antinociceptive effects of acute intrathecal (i.t.) injections of morphine on tail-flick latencies in naïve rats and chronic morphine-treated rats given i.t. infusions. Shown are (A) the per cent maximum possible effect (%MPE) obtained for the period of peak morphine effect, and (B) the area under the curves (AUCs) for over the entire 60 min testing session, obtained after acute i.t. injection of 3, 10 or 30 μg morphine in various groups of rats. Groups include naïve rats, or in rats that received chronic s.c. morphine treatment concomitantly with chronic i.t. mGluR1 AS, mGluR MIS or ACSF. **P<0.01, ***P<0.001 represent values that are significantly different from the pre-treatment naïve group, and †P<0.05; ††P<0.01; †††P<0.001 represent values that are significantly different from the mGluR1 AS group.
Figure 2
Figure 2
Time course of the antinociceptive effects of (A) acute s.c. (10 mg kg−1) and (B) acute i.t. (30 μg) injection of morphine on tail-flick latencies in rats. Shown are the % maximum possible effect (%MPE) scores every 15 min over the 60 min testing session obtained after acute s.c. or i.t. morphine injection in naïve rats, or in rats that received chronic s.c. morphine treatment concomitantly with chronic i.t. infusion of mGluR1 AS, mGluR1 or ACSF. **P<0.01 represent values that are significantly different from the pre-treatment group. ††P<0.01 represents values significantly different from that of the mGluR1 AS-treated group.
Figure 3
Figure 3
(A) The effects of mGluR1 AS, mGluR1 MIS, and ACSF infusion at the lumbar level of the spinal cord on the quantification of binding density of the mGluR1 receptor proteins in spinal cord tissues. The quantification of binding density of mGluR1 receptor proteins is obtained after incubating the spinal cord tissue with an mGluR1 antibody. The decrease in protein binding intensity as compared to naïve animals is 18±17% for the MIS-treated group, 3±3% for the ACSF-treated group, and 42±8 for the AS-treated group (*P<0.05 represents values that are significantly different from ACSF treated group). (B) Representative immunoblots of the mGluR1 protein levels from the four different treatment groups. Shown are immunoblots using mGluR1 antibodies after gel electrophoresis of lysates from spinal cord segments L3-L6 of naïve, ACSF-, AS- or MIS-treated animals. Bands at (140 kD) represent mGluR1 protein.
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