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