Abstract
Loperamide reverses signs of mechanical hypersensitivity in an animal model of neuropathic pain suggesting that peripheral opioid receptors may be suitable targets for the treatment of neuropathic pain. Since little is known about loperamide effects on the responsiveness of primary afferent nerve fibers, in vivo electrophysiological recordings from unmyelinated afferents innervating the glabrous skin of the hind paw were performed in rats with an L5 spinal nerve lesion or sham surgery. Mechanical threshold and responsiveness to suprathreshold stimulation were tested before and after loperamide (1.25, 2.5 and 5 µg in 10 µl) or vehicle injection into the cutaneous receptive field. Loperamide dose-dependently decreased mechanosensitivity in unmyelinated afferents of nerve-injured and sham animals, and this effect was not blocked by naloxone pretreatment. We then investigated loperamide effects on nerve conduction by recording compound action potentials in vitro during incubation of the sciatic nerve with increasing loperamide concentrations. Loperamide dose-dependently decreased compound action potentials of myelinated and unmyelinated fibers (ED50 = 8 and 4 µg/10 µl, respectively). This blockade was not prevented by pre-incubation with naloxone. These results suggest that loperamide reversal of behavioral signs of neuropathic pain may be mediated, at least in part, by mechanisms independent of opioid receptors, most probably by local anesthetic actions.
Highlights
The treatment of neuropathic pain continues to be a challenge with less than a third of patients obtaining satisfactory relief from presently available drugs [1]
The effect of local loperamide injection on mechanosensitivity was tested in a total of 36 afferents, 24 of which were recorded in lesioned animals
To test if the observed loperamide effect on the mechanosensitivity of unmyelinated fibers were mediated by an opioid mechanism, we investigated if pretreatment with naloxone (either 4 mg in 10 ml (n = 3) or 80 mg in 20 ml (n = 10)) is able to prevent the inhibitory effects of loperamide in 13 unmyelinated afferents from unlesioned animals (n = 8)
Summary
The treatment of neuropathic pain continues to be a challenge with less than a third of patients obtaining satisfactory relief from presently available drugs [1]. Opioids have been recommended as second line therapy for neuropathic pain, the beneficial effects of chronic use of systemic and intrathecal opioids in the treatment of neuropathic pain remains controversial [2,3,4]. Initial reports suggested that patients with cancer pain, including those with a neuropathic component, might benefit from treatment with chronic intrathecal morphine [5,6]. More recent controlled trials with oral opioids by us [9] and other investigators [10,11,12] and case studies of intrathecal opioid treatment of neuropathic pain [13,14,15] demonstrate good pain relief even after long-term administration. Concerns regarding addiction and the potential for abuse of this class of drugs have limited its widespread acceptance and use
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