Peripheral component in the enhanced antinociceptive effect of systemic U-69,593, a κ-opioid receptor agonist in mononeuropathic rats

doi:10.1016/S0014-2999(98)00597-4

European Journal of Pharmacology

Volume 357, Issues 2–3, 18 September 1998, Pages 171-178

https://doi.org/10.1016/S0014-2999(98)00597-4 Get rights and content

Abstract

The contribution of a peripheral action of the κ-opioid receptor agonist U-69,593 (trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) cycloexil] benzene-acetamide methanesulfonate) in the augmented antinociceptive effect of this substance was investigated in a well-established rat model of peripheral unilateral neuropathy (chronic constriction of the common sciatic nerve). Relatively low dose of systemic U-69,593 (0.75 mg/kg intravenous (i.v.)) and intraplantar (i.pl.) low doses of specific antagonists of κ-(nor-binaltorphimine) or μ-(d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH₂: CTOP) opioid receptors were used. Vocalization thresholds to paw pressure were used as a nociceptive test. The i.pl. injection of nor-binaltorphimine (10–15 μg injected into the nerve-injured hind paw) had no effect on the antinociceptive effect of U-69,593. Higher doses (20–30 μg i.pl. nor-binaltorphimine) significantly reduced the effect of U-69,593 on this paw but not on the contralateral paw, an effect which plateaued at 30 μg. By contrast, the i.pl. injection of CTOP (1 μg into the nerve-injured paw) had no effect on U-69,593 antinociception, whereas it reduced the effect of systemic morphine in these animals. The doses of nor-binaltorphimine used, injected into the contralateral paw or i.v., failed to modify the antinociceptive effects of U-69,593 on either paw. These results provide evidence for a peripheral component in the enhanced antinociceptive effect of systemic U-69,593 in this model of neuropathic pain.

Introduction

Traditionally, opioid analgesia has been attributed to the activation of opioid receptors exclusively within the central nervous system. Over the past 15 years, however, a large number of studies have discovered and characterized peripheral opioid actions. Such effects occur primarily in inflamed but also in normal tissue (Kayser et al., 1990, Kayser and Guilbaud, 1994; Antonijevic et al., 1995; Kolesnikov et al., 1996), and have been found both in animal experiments and under clinical conditions in patients (Stein and Yassouridis, 1997). Opioid receptors have been demonstrated on peripheral terminals in thinly myelinated and unmyelinated sensory nerves in animals (Fields et al., 1980; Hassan et al., 1993; Coggeshall et al., 1997) and opioid receptor messenger ribonucleic acid (mRNA) has been detected in dorsal root ganglia, which contain the cell bodies of primary afferent neurons (Maekawa et al., 1994; Schäfer et al., 1995; Buzas and Cox, 1997). All three opioid receptor types (μ, δ, κ) can be functionally active in peripheral tissues (Barber and Gottschlich, 1992; Stein, 1993, Coggeshall et al., 1997).

Various animal models have been developed to investigate neuropathic pain. Of these, the well-established rat model of peripheral mononeuropathy produced by persistent moderate constriction of the common sciatic nerve (Bennett and Xie, 1988; Attal et al., 1990) has been studied extensively in our laboratory. We have shown that in this model, systemic morphine and selective agonists at μ-([d-Ala2,N-MePhe4,Gly5-ol]-enkephalin: DAMGO), δ-([d-Thr2,Leu5]-enkephalin-Thr: DTLET and [d-Cys(StBu)2,Leu5]-enkephalin-Thr(OtBu)]: BUBUC) and κ-(trans-3,4-dichloro-N-methyl-N-[7-(1-pyrrolidinyl) cycloexil] benzene-acetamide methanesulfonate: U-69,593) opioid receptors produce dose-dependent effects on the vocalization threshold to paw pressure test and have an enhanced effect on the nerve-injured side (Neil et al., 1990; Attal et al., 1991; Desmeules et al., 1993; Catheline et al., 1996a, Catheline et al., 1996b; Idänpään-Heikkilä et al., 1997). The contribution of a peripheral opioid receptor mechanism in the enhanced antinociceptive effect of systemic morphine has been demonstrated (Kayser et al., 1995), which could be mediated not only by μ- but also by κ-opioid receptors (Catheline et al., 1996a). Consistent with these findings, we also found a significant effect of the peripherally selective κ-opioid receptor agonist (R, S)-N-]2-(N-methyl-3,4-dichloro-phenylacetamido)-2-(3-carboxyphenyl)-ethyl]pyrrolidine hydrochloride: ICI 204408) on the neuropathic rats, which was reversed by i.pl. nor-binaltorphimine (Keı̈ta et al., 1995).

Following our investigation on peripherally mediated opioid analgesia, we have investigated in the present study the antinociceptive activity of systemic U-69,593 (0.75 mg/kg i.v.) after peripheral application of low doses of specific antagonists of μ- and κ-opioid receptors (d-Phe-Cys-Tyr-d-Trp-Orn-Thr-Pen-Thr-NH₂: CTOP and nor-binaltorphimine, respectively) by using the measure of the vocalization thresholds to paw pressure as a nociceptive test in the chronic constriction injury model. Even though the antinociceptive efficacy of κ-opioid receptor agonists has been studied to some extent under both normal and inflammatory conditions (Stein et al., 1988, Stein et al., 1989; Taiwo and Levine, 1991; Kolesnikov et al., 1996), the experimental evidence on neuropathic rats is still sparse.

Section snippets

Animals

Male Sprague–Dawley rats (Charles River, Saint-Aubin-lès-Elbeuf, France), n=63, weighing 175 to 200 g on arrival, were used. The rats were housed five in a cage on a 12-h light/12-h dark cycle (lights on at 0700). The ambient temperature was kept at 22°C, and the rats had free access to standard laboratory food and tap water. The animals were allowed to habituate to the housing facilities for at least 1 week before the experiments were begun. The Guidelines of the Committee for Research and

Results

Before the nerve ligature, the mean vocalization thresholds to paw pressure (336±10 g and 333±7 g, n=63) obtained from the left and right hind paws respectively, did not differ. In agreement with previous studies (Desmeules et al., 1993; Kayser et al., 1995; Catheline et al., 1996a, Catheline et al., 1996b; Idänpään-Heikkilä et al., 1997), at week 2 after the nerve ligature, the mean vocalization threshold to paw pressure of the nerve-injured hind paw was decreased to 237±3 g (71±3% of the

Discussion

Two weeks after the surgery, the rats with the chronic constriction injury of the sciatic nerve exhibited abnormal pain sensitivity, with decreased thresholds to mechanical stimulation, as shown previously (Attal et al., 1990; Desmeules et al., 1993; Kayser et al., 1995; Catheline et al., 1996a, Catheline et al., 1996b; Idänpään-Heikkilä et al., 1997). In the control group of rats receiving i.pl. saline, the κ-opioid receptor agonist U-69,593 increased the vocalization thresholds to paw

Acknowledgements

This study was partly supported by the Association pour la Recherche sur le Cancer.

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The dorsal column pathway consists of direct projections from primary afferents and of ascending fibers of the post-synaptic dorsal column (PSDC) cells. This pathway mediates touch but may also mediate allodynia after nerve injury. The role of PSDC neurons in nerve injury-induced mechanical allodynia is unknown. Repetitive gentle, tactile stimulus or noxious pinch was applied to the ipsilateral hindpaw of rats with spinal nerve ligation (SNL) or sham surgery that had previously received tetramethylrhodamine dextran in the ipsilateral n. gracilis. Both touch and noxious stimuli produced marked increases in FOS expression in other cells throughout all laminae of the ipsilateral dorsal horn after nerve injury. However, virtually none of the identified PSDC cells expressed FOS immunofluorescence in response to repetitive touch or pinch in either the nerve-injured or sham groups. In contrast, labeled PSDC cells expressed FOS in response to ureter ligation and labeled spinothalamic tract (STT) cells expressed FOS in response to noxious pinch. Identified PSDC neurons from either sham-operated or SNL rats did not express immunoreactivity to substance P, CGRP, NPY, PKCY, MOR, the NK1 and the NPY-Y1 receptor. Retrogradely labeled DRG cells of nerve injured rats were large diameter neurons, which expressed NPY, but no detectable CGRP or substance P. Spinal nerve injury sensitizes neurons in the spinal dorsal horn to repetitive light touch but PSDC neurons apparently do not participate in touch-evoked allodynia. Sensitization of these non-PSDC neurons may result in activation of projections integral to the spinal/supraspinal processing of enhanced pain states and of descending facilitation, thus priming the central nervous system to interpret tactile stimuli as being aversive.

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Peripheral component in the enhanced antinociceptive effect of systemic U-69,593, a κ-opioid receptor agonist in mononeuropathic rats

Abstract

Introduction

Section snippets

Animals

Results

Discussion

Acknowledgements

Pain

Pain

Pain

J. Neurol. Sci.

J. Neuroimmunol.

Neuron

Neuroscience

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neurosci. Lett.

Brain Res.

Pain

Neuroscience

Eur. J. Pharmacol.

Neurosci. Lett.

Pain

Pain

Neuroscience

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neurosci. Lett.

Exp. Neurol.