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 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.
Nichols
Michael L
ML
Department of Pharmacology, The University of Arizona Pain Institute, Health Sciences Center, Tucson, AZ 85724, USA Department of Anesthesiology, The University of Arizona Pain Institute, Health Sciences Center, Tucson, AZ, USA Synthelabo Recherche, 92504 Rueil, Malmaison, France.
Lopez
Yvan
Y
Ossipov
Michael H
MH
Bian
Di
D
Porreca
Frank
F
D000701:Analgesics, Opioid / Q000627:therapeutic use*; D000818:Animals; D003250:Constriction; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D004399:Dynorphins / Q000276:immunology*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D007106:Immune Sera; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000627:therapeutic use*; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement; D010446:Peptide Fragments / Q000276:immunology*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014110:Touch / Q000502:physiology
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D007106:Immune Sera; D010446:Peptide Fragments; D016291:Dizocilpine Maleate; C026843:dynorphin (1-13); D004399:Dynorphins; D009020:Morphine