Peripheral effects of morphine in neuropathic rats: role of sympathetic postganglionic nerve fibers

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Abstract

We studied the contribution of peripheral opioid receptors to the morphine-induced antinociception in rats with a spinal nerve ligation-induced neuropathy. Intraplantar (i.pl.) injection of morphine produced a stronger suppression of nociceptive reflex responses of the neuropathic limb following ipsilateral, than contralateral, administration, whereas the morphine-induced effect on the control limb was independent of the injection side. Antinociception induced by systemically administered morphine was significantly attenuated by i.pl. injection of a peripherally acting opioid receptor antagonist in neuropathic but not in sham-operated rats. Following chemical sympathectomy with 6-hydroxydopamine, antinociception was achieved at a lower dose ipsilaterally, than contralaterally, following i.pl. administration of morphine, and the morphine-induced antinociception was attenuated by a peripherally acting opioid receptor antagonist. These results indicate that peripheral opioid receptors may contribute to the morphine-induced antinociception in the spinal nerve ligation-induced model of neuropathy. Sympathectomy of the neuropathic limb may underlie, at least partly, the increased peripheral efficacy of morphine in neuropathy.

Introduction

A peripherally acting analgesic drug might be highly beneficial in treating pathophysiological pain, since it provides a possibility to selectively treat pain with minor central side-effects. There is abundant evidence indicating that peripheral mechanisms may significantly contribute to the morphine-induced antinociceptive effect under inflammatory conditions Ferreira and Nakamura, 1979, Joris et al., 1987, Stein et al., 1988. Moreover, morphine has been shown to have peripheral antinociceptive actions in animals with the chronic constriction model of mononeuropathy Kayser et al., 1995, Catheline et al., 1996. Some studies suggest that chromic gut-induced inflammation may actually induce the hypersensitivity observed in chronic constriction model of neuropathy (Maves et al., 1993). In addition, other recent studies have emphasized the role of inflammation in experimental models of neuropathy (Bennett, 1999). This raises the question whether the peripheral antinociceptive actions observed in mononeuropathic animals were due to inflammation or neuropathy. Therefore, we determined the peripheral action of morphine in another model of neuropathy that is caused by tightly ligating two spinal nerves (Kim and Chung, 1992). A sham operation of the spinal nerves does not produce neuropathic symptoms suggesting that nerve injury might have a more important role in this model of neuropathy. This hypothesis is supported by the histological findings that a visible inflammatory reaction of the peripheral nerves appears less marked in the spinal nerve ligation model (Röyttä et al., 1999) than in the chronic constriction injury model (Luukko et al., 1994).

The method for the induction of neuropathy, ligation of the peripheral or spinal nerve, leads to an accompanying destruction of somatic as well as sympathetic nerve fibers (Baron et al., 1988). The possible consequences of nerve ligation on peripheral morphine sensitivity might be as well to injury of somatic nerves, autonomic nerves, or both. In the present study, we attempted to determine the contribution of the injury of somatic vs. autonomic nerves to the possible peripheral action of morphine by comparing the effect of nerve ligation with that produced by a chemical sympathectomy.

Section snippets

Materials and methods

The experiments were performed with adult, male Hannover Wistar rats (weight 200–300 g; The Finnish Laboratory Animal Center, Kuopio, Finland). The experimental protocol adhered to the European Community guidelines for the use of experimental animals and it was accepted by the Institutional Animal Care Committee of the University of Helsinki and the Regional Government of Southern Finland. The animals were housed in polycarbonate cages with a deep layer of sawdust, one to three animals in each

Baseline responses in different experimental groups

In a test of tactile allodynia (the monofilament test), the median baseline hindlimb withdrawal threshold ipsilateral to the spinal nerve ligation was 2.1 g (range 1.4–3.6 g), whereas in the contralateral (unoperated) hindlimb of the same animals the median threshold was 18.1 g (range 12.5–20.1 g). The corresponding threshold was 20.5 g (range 12.5–38 g) in the sham-operated group and 21.5 g (range 7.4–46.5 g) in the 6-hydroxydopamine-pretreated group. The monofilament-induced hindlimb

Discussion

According to the present results, mechanical hypersensitivity in animals with a spinal nerve ligation-induced neuropathy is more effectively suppressed following peripheral administration of morphine into the neuropathic than the contralateral hind paw. Moreover, administration of a peripherally acting opioid receptor antagonist, naloxone methiodide, into the neuropathic hind paw reversed the antiallodynic and antihyperalgesic effect induced by systemically administered morphine in the

Acknowledgements

We wish to thank Dr. E. Mecke for his help in the experiments. This study was supported by the Sigrid Jusélius Foundation, Helsinki, and the Academy of Finland.

References (16)

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