Enhancement of the antiallodynic and antinociceptive efficacy of spinal morphine by antisera to dynorphin A (1–13) or MK-801 in a nerve-ligation model of peripheral neuropathy

Abstract

Neuropathic pains arising from peripheral nerve injury can result in increased sensitivity to both noxious and non-noxious stimuli and are accompanied by a number of neuroplastic alterations at the level of the spinal cord including upregulation of neurotransmitters including dynorphin, cholecystokinin and neuropeptide Y. Additionally, such pain states appear to be associated with activation of excitatory amino acid receptors including the N-methyl-D-aspartate (NMDA) receptor. Neuropathic pains have often been classified as 'opioid resistant' in both clinical and laboratory settings. As it is known that dynorphin produces 'non-opioid' effects through interaction with NMDA receptors and this peptide is upregulated after peripheral nerve injury, the present studies were undertaken to determine the possible importance of this substance in the neuropathic state. Nerve injury was produced in rats by tight ligation of the L5 and L6 spinal roots of the sciatic nerve. Catheters were inserted for the intrathecal (i.t.) delivery of drug to the lumbar spinal cord. Tactile allodynia was determined by measuring responses to probing the plantar surface of the affected limb with von Frey filaments, and acute nociception was determined in the 55 degrees C hot-water tail-flick test in nerve-ligated and sham-operated subjects. Intrathecal administration of MK-801 or antisera to dynorphin A (1-13) did not alter the tactile allodynia associated with nerve-ligation injury or the baseline tail-flick latency in either sham-operated or nerve-injured animals. As previously reported, i.t. morphine did not alter tactile allodynia and showed reduced potency and efficacy to block the tail-flick reflex in nerve-injured animals. Co-administration, however, of i.t. morphine with MK-801, or i.t. antisera to dynorphin A (1-13) given prior to morphine elicited both a full antiallodynic response and a complete block of the tail-flick reflex in nerve-injured animals. These results suggest that tonic activation of NMDA receptors, following peripheral nerve injury, is involved with the attenuation of the effectiveness of spinal morphine in a model of neuropathic pain. Additionally, this tonic NMDA activity may be mediated, in part, by increased levels of endogenous dynorphin associated with peripheral nerve injury.

The antinociceptive effect of combined systemic administration of morphine and the glycine/NMDA receptor antagonist, (+)‐HA966 in a rat model of peripheral neuropathy

“…This result ®ts in well with results from previous studies in di erent models of neuropathic pain using either systemic (Advokat & Rhein, 1993;Kauppila et al, 1998) or intrathecal (Yamamoto & Yaksh, 1992;Ossipov et al, 1995;Nichols et al, 1997) routes of administration. In these studies, however, the NMDA receptor antagonist failed to modulate the e ect of morphine in the contralateral paw (Yamamoto & Yaksh, 1992) or in sham-operated rats (Ossipov et al, 1995).…”

“…It has been shown that NMDA receptor antagonism reverses the ine ectiveness of morphine in depressing dorsal horn neuronal activity (Chapman & Dickenson, 1992). In addition, the sensitivity of thermal hyperalgesia (Yamamoto & Yaksh, 1992;Ossipov et al, 1995) and mechanical allodynia (Nichols et al, 1997) to intrathecal morphine can be restored by concomitant intrathecal administration of a NMDA receptor antagonist in di erent models of neuropathic pain.…”

An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat

“…It is widely recognized that spinal glial activation following peripheral nerve injury or inflammation may be involved in altered spinal processing of sensory information (Kajander et al, 1990;Nichols et al, 1997;Aldskogius et al, 1999;Watkins et al, 2001) and the development of tactile allodynia (Jin et al, 2003;Tsuda et al, 2003). In the current study, an increase in the levels of CD11b-IR microglia and GFAP-IR astrocytes was first observed at day six days post-infusion in the dorsal horn of the spinal cord of paclitaxel-treated rats.…”

Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated μ-Opioid Receptor–Gs Coupling

“…Animal models of neuropathic pain have shown that nerve injury induces a host of pronociceptive, neuroplastic changes, including an upregulation of dynorphin in the spinal cord, enhanced levels of cholecystokinin, increased activation of phosphorylated p38 MAP kinase, and increased content and evoked release of substance P and CGRP. [1][2][3][4]10,34,52,66,80 Upregulation of cytokine receptor mRNA in the sciatic nerve and dorsal root ganglion after partial spinal nerve ligation has been noted, and SNL has also been reported to decrease MOR density in injured peripheral axons in the ipsilateral Lamina I of dorsal horn, leading to changes in presynaptic-and postsynapticevoked responses of MOR-containing fiber. 2,46,59 These synaptic changes include a decrease in presynaptic MOR-mediated inhibition, reduced inhibition of the miniature EPSP in substantia gelatinosa neurons, a shortened afterhy-perpolarization duration in C-fibers in the L 5 dorsal root ganglion, and increased repetitive firing of Aδ-fibers during sustained depolarization.…”