Development of antinociceptive tolerance and changes of opioid receptor ligand binding in central nervous system of the mouse forced to single and repeated swimming in the cold water

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Abstract

The present study was designed to characterize underlying mechanism involved in the development of tolerance in the production of antinociceptive effect induced by repeated cold water swimming stress (CWSS) using the tail-flick test. Mice were forced to swim at 4 °C for 3 min and the tail-flick test was performed 5, 10, 20, and 30 min after the swimming. The profound antinociception was induced by a single CWSS. However, when the mice were exposed to CWSS repeatedly seven times, they showed a tolerance in the production of antinociception. In the opioid receptor binding study, Bmax of delta opioid receptor (DOR) was decreased in the brainstem, midbrain and the spinal cord areas by both a single and repeated CWSS, without altering Kd value. However, Bmax values of mu opioid receptor (MOR) and kappa opioid receptor (KOR) were increased in the brainstem, midbrain and spinal cord regions by repeated CWSS, without changing Kd values. Our results suggest that the development of tolerance in the production of antinociception in mice forced to the repeated CWSS may be, at least, due to the reduction of DOR number in the brainstem, midbrain and the spinal cord regions.

Introduction

Antinociception produced in animals after exposure to a variety of aversive events has been well known. Several lines of evidence have demonstrated that antinociceptive properties have been characterized in water swimming stress model. For example, exposure of animals to swimming stress in cold water produces antinociception measured in various pain models including the tail-flick 10., 20., 30., formalin 8., 9., 11., and writhing tests [21].

Currently, the exact mechanisms involved in cold water swimming stress (CWSS)-induced antinociception have not been revealed. However, several authors have reported that supraspinal or spinal opioid receptors appear to be related to CWSS-induced antinociception 12., 28., 29.. It is well known that opioids produce a strong antinociception (for review, see 15., 31.) and repeated administration of opioids shows the development of tolerance in the production of antinociception (for review, see 1., 3., 14.). If opioids are involved in CWSS-induced antinociception, it is speculated that the antinociceptive tolerance may be developed when mice are forced to the repeated CWSS.

Thus, in the present study, the antinociceptive profiles of mice forced to a single and repeated CWSS was characterized. Furthermore, mu-, delta-, and kappa-opioid receptor binding properties were assessed in mice forced to a single and repeated CWSS.

Section snippets

Experimental animals

Male ICR mice (25–30 g) from Daehan Laboratories (Seoul, Korea) were used for all experiments. The animals were housed five per cage in a room maintained at 22±0.5 °C with an alternating 12 h light:dark cycle. Food and water were available ad libitum. Each mouse was used only once.

Cold water swimming stress

The mice were forced to swim in cold (4 °C) water for 3 min. The mice were allowed to swim in a container 15 cm in diameter and 20 cm tall with water filled to a depth of 11 cm. Repeated swimming was performed twice per day

Antinociceptive profiles of mice forced to a single and repeated CWSS

Five minutes after the swimming, mice were subjected for the tail-flick test. As shown in Fig. 1, a single swimming at 4 °C produced the inhibition of the tail-flick response. The inhibition of the tail-flick response induced by swimming stress reached a maximum 10 min after the swimming, gradually began to decrease, and returned to the control level 30 min after the swimming. However, no profound antinociception was produced in mice forced to the repeated CWSS (Fig. 1).

Opioid receptor binding properties in mice forced to a single and repeated CWSS

As shown in Table 1, Table 3

Discussion

The results of the present study clearly demonstrate that CWSS produces a profound antinociception in a tail-flick test and the antinociceptive tolerance is developed, when mice are forced to a repeated (up to seven times) CWSS. Our results are, at least in part, similar to the studies by other groups. For example, Truesdell and Bodnar [27] have reported that exposing rats to a 3.5 min swimming at 2 °C water significantly increased tail-flick withdrawal latencies for up to 60 min following the

Acknowledgements

This work was supported by the Research Grant from Hallym University, South Korea.

References (31)

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