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Changes in Analgesia-Producing Mechanism of Repeated Cold Stress Loading in Mice

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Abstract

Functional changes in opioid receptors involved in analgesia of repeated cold stress (RCS)-loaded mice were investigated. The antinociceptive potency of morphine (4 mg/kg, PO) was not affected in normal mice by norbinaltorphimine (10 mg/kg, SC), but treatment with this agent resulted in a lower level of morphine-induced antinociception in RCS-loaded animals. The antinociceptive activity of U-50488H (3 mg/kg, SC) was increased in RCS-loaded mice. In contrast to hypersensitivity to U-50488H (1 and 10 μg, IT) noted in RCS-loaded mice, the antinociception induced by DAMGO (0.1 and 1 μg, ICV) was reduced compared to that of normal animals. Diazepam (1 mg/kg/day SC) was given during RCS loading, and this agent prevented the development of hyperalgesia and the decrease in the antinociceptive activity of DAMGO (1 μg, ICV) in RCS-loaded mice, but there was no effect on the enhancement of the antinociceptive potency of U-50488H (10 μg, IT). These results indicate that the RCS-loaded mice were hyposensitive to supraspinal μ-opioid receptor-mediated antinociception, whereas their antinociceptive activities through κ-opioid receptor in the spinal cord were increased. Hypofunction of the supraspinal μ-opioid receptor due to anxiety may explain the mechanism involved in the lowering of the nociceptive threshold in RCS-loaded animals.

Section snippets

Animals

Male ddY mice weighing 20–25 g at the beginning of the experiment were used. Four animals were housed per cage under a 12-h light and dark cycle (lights on between 0700–1900) and had free access to food and water throughout the experiments.

Repeated Cold Stress (RCS)

Kuraishi et al. (15) reported that sufficient and constant decreases in the nociceptive threshold were induced 3 days after initiation of RCS loading. In our experiment, the nociceptive threshold was also decreased 3 days after initiation of RCS-loading (Fig.

Effects of nor-BNI on the Antinociceptive Action of Morphine in RCS-Loaded and Normal Mice

The antinociceptive effect of morphine (4 mg/kg, PO), was not affected by RCS loading. Pretreatment with nor-BNI (10 mg/kg, SC), a highly selective antagonist of κ-opioid receptors, did not influence the antinociceptive effects of morphine in the normal (untreated) mice, whereas it reduced the potency of morphine-induced analgesia to 51% of that in the saline-treated group in RCS-loaded mice (Fig. 2).

Effects of RCS Loading on the Antinociceptive Activity of U-50488H

The antinociceptive activity of U-50488H (3 mg/kg, SC), a κ-opioid agonist, in the RCS-loaded

Discussion

This study is the first report demonstrating hyporesponsiveness of the supraspinal μ-opioid receptors and the enhancement of the spinal κ-opioid receptor-mediated antinociception in RCS-loaded animals.

The antinociceptive activity of morphine was decreased by pretreatment with nor-BNI in RCS mice, indicating that nearly half of the activity might be mediated by κ-opioid receptors in those animals. The increase in the antinociceptive activity of U-50488H in RCS-loaded mice supported that the role

Acknowledgements

This study was supported by Aging and Health research funds from the Ministry of Health and Welfare.

References (32)

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