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

Neuropathic pains arising from peripheral nerve injury can result in i ncreased sensitivity to both noxious and non-noxious stimuli and are a ccompanied by a number of neuroplastic alterations at the level of the spinal cord including upregulation of neurotransmitters including dyn orphin, cholecystokinin and neuropeptide Y. Additionally, such pain st ates appear to be associated with activation of excitatory amino acid receptors including the N-methyl-D-aspartate (NMDA) receptor. Neuropat hic pains have often been classified as 'opioid resistant' in both cli nical 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 stud ies were undertaken to determine the possible importance of this subst ance in the neuropathic state. Nerve injury was produced in rats by ti ght ligation of the L5 and L6 spinal roots of the sciatic nerve. Cathe ters were inserted for the intrathecal (i.t.) delivery of drug to the lumbar spinal cord. Tactile allodynia was determined by measuring resp onses to probing the plantar surface of the affected limb with von Fre y 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 i njury or the baseline tail-flick latency in either sham-operated or ne rve-injured animals. As previously reported, i.t. morphine did not alt er tactile allodynia and showed reduced potency and efficacy to block the tail-flick reflex in nerve-injured animals. Co-administration, how ever, 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 respon se and a complete block of the tail-flick reflex in nerve-injured anim als. These results suggest that tonic activation of NMDA receptors, fo llowing peripheral nerve injury, is involved with the attenuation of t he effectiveness of spinal morphine in a model of neuropathic pain. Ad ditionally, this tonic NMDA activity may be mediated, in part, by incr eased levels of endogenous dynorphin associated with peripheral nerve injury.