Intravenous morphine does not modify dorsal horn touch-evoked allodynia in the mononeuropathic rat: a Fos study
Introduction
Pain arising from nerve injury is difficult to treat and the effectiveness of opioids in this kind of pain is still controversial (Arnér and Meyerson, 1988, Portenoy et al., 1990, Foley and Portenoy, 1991, Kupers et al., 1991, Rowbotham et al., 1991, Jadad et al., 1992, Cherny et al., 1994, Moulin et al., 1996, Benedetti et al., 1998, Kingery, 1997, Dellemijn, 1999). Multiple pathophysiological mechanisms associated with various neuropathies could partly explain the discrepancies in opioid effectiveness described in the literature (Dubner, 1991, Besson et al., 1993).
In an attempt to clarify the mechanisms of pain and associated processes following peripheral nerve injury, animal models of chronic neuropathic pain have been developed over the last decade (Bennett and Xie, 1988, Seltzer et al., 1990, Kim and Chung, 1992, Vos et al., 1994). These different models of neuropathy of peripheral origin have allowed the relative efficacy of opioids in neuropathic pain to be established. Indeed, in the chronic constriction injury (CCI) model, it has been demonstrated that systemic administration of opioids alleviates spontaneous pain-related behaviour (Jazat and Guilbaud, 1991, Kupers et al., 1992), cold allodynia (Hedley et al., 1995, Jasmin et al., 1998; see however, Lee et al., 1994), and mechanical (Attal et al., 1991, Desmeules et al., 1993, Koch et al., 1996) and thermal hyperalgesia (Lee et al., 1994, Backonja et al., 1995). However, the intrathecal (i.t.) injection of morphine did not produce any effect on thermal hyperalgesia when evaluated by the paw withdrawal latency to radiant heat in the CCI model (Mao et al., 1995). This lack of efficacy of i.t. administration of opioids was also observed in the spinal nerve ligation model (Lee et al., 1995, Bian et al., 1995, Ossipov et al., 1995, Wegert et al., 1997, Nichols et al., 1997). In this model, intracerebroventricular (i.c.v.) or systemic but not i.t. morphine had antinociceptive effects on mechanical allodynia evaluated by von Frey filaments (Lee et al., 1995, Bian et al., 1995). This is similar to the finding that antinociceptive effects of morphine on thermal hyperalgesia are reduced in spinal nerve injury rats as compared to normal rats (Wegert et al., 1997). However, in a recent electrophysiological study, it has been demonstrated that i.t. morphine had an enhanced potency on the C fibre-evoked and noxious natural stimuli-evoked neuronal response of spinal nerve-ligated rats (Suzuki et al., 1999). All these studies show that the efficacy of opioids is variable and seems to depend on several factors: the model, the nature and intensity of the stimuli (mechanical and thermal allodynia, hyperalgesia), and the route of administration used.
The majority of the data has been derived from behavioural studies, in which it is sometimes difficult to discriminate the psychomimetic and/or motor effects from the analgesic effects of the drugs. To our knowledge, there is only one electrophysiological study on the effects of opioids in the spinal cord of neuropathic rats (Suzuki et al., 1999). This is not surprising considering the complex changes in dorsal horn neuronal activity of CCI rats (Palecek et al., 1992, Laird and Bennett, 1993), and spinal nerve-ligated rats (Chapman et al., 1998). To overcome these difficulties, we have used the detection of c-Fos protein, which could be considered as an indirect marker of nociceptive processes at the spinal cord level (see Refs. in Chapman and Besson, 1997). This technique has several advantages: (1) it can be performed in freely moving animals; (2) it depends on the activation of numerous neurones located in the two main areas (superficial and deep dorsal horn) involved in spinal pain processes; and (3) it is applicable for the study of the effects of established or potential analgesic drugs in normal and various inflammatory pain states.
This technique has allowed us to reveal mechanical allodynia in awake CCI rats (Catheline et al., 1999a, Catheline et al., 1999b). Indeed, we demonstrated that a non-noxious mechanical stimulation (consisting of repeated stroking of the flat surface of the hindpaw) induced Fos expression in superficial and deep dorsal horn of CCI rats 14 days after the nerve injury. This type of stimulation did not induce Fos expression at the spinal cord level of normal or sham-operated rats.
Thus, in the present study, we have evaluated the effects of various doses of intravenous (i.v.) morphine on stroking-induced spinal Fos expression in CCI rats. We have also tested the effects of 3 mg/kg i.v. of morphine on heat stimulation-induced Fos expression in CCI rats.
Section snippets
Animals
Adult male albino Sprague–Dawley rats (Charles River, France; n=111) weighing 200–250 g were housed six per cage in a room with a controlled temperature (22±1°C) and a 12 h alternating light/dark cycle. Food and water were made available continuously. Guidelines on ethical standards for investigations of experimental pain in conscious animals were followed (Zimmermann, 1983).
Surgical procedure
The neuropathy was produced on the right hindpaw according to the method described by Bennett and Xie (1988). Under
Vocalization to paw pressure
Thirteen days after the surgical procedure, the mean vocalization threshold to paw pressure of sham-operated rats was 349±11 g and 353±7 g for the right and the left paw, respectively (NS, unpaired t-test). For CCI rats, the mean vocalization threshold to paw pressure was 252±4 g for the nerve-injured paw and 361±3 g for the contralateral paw (P<0.05, unpaired t-test). All of the CCI rats selected for the Fos experiments presented clear mechanical hyperalgesia (32% decrease in the vocalization
Discussion
This study demonstrates that the expression of Fos protein induced by a non-noxious stimulation in both superficial and deep dorsal horn laminae of neuropathic rats is morphine-insensitive. Intravenous administration of 0.3, 1 or 3 mg/kg of morphine did not modify the number of Fos-LI neurones evoked by stroking of the nerve-injured paw. In contrast, 3 mg/kg i.v. of morphine reduced by 30% the number of Fos-LI neurones induced by noxious heat stimulation in CCI rats. This effect of systemic
Acknowledgements
This work was supported by l'Institut National de la Santé et de la Recherche Médicale (INSERM). G.C. and S.L.G. were respectively supported by a Biomed 2 contract (no. BMH4-CT950172) and by the Ministère de l'Enseignement Supérieur de la Recherche, et de la Technologie. We thank Dr V. Chapman and A. Dickenson for their helpful suggestions.
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