Loss of antiallodynic and antinociceptive spinal/supraspinal morphine synergy in nerve-injured rats: restoration by MK-801 or dynorphin antiserum.
The co-administration of morphine at spinal (i.th.) and supraspinal (i.c.v.) sites to the same rat produces antinociceptive synergy, a phenomenon which may underlie the clinical analgesic utility of this drug. In animals with peripheral nerve injury, however, the antinociceptive potency and efficacy of i.th. morphine is significantly decreased. Here, the possible loss of spinal/supraspinal morphine antinociceptive synergy and relationship to elevation of spinal dynorphin content was studied. Ligation of lumbar spinal nerves resulted in elevated dynorphin in the ipsilateral lumbar and sacral spinal cord. In sham-operated rats supraspinal/spinal co-administration of morphine produced synergistic antinociception which was unaffected by i.th. MK-801 or dynorphin A((1-17)) antiserum. In nerve-injured rats, i.th. morphine was inactive against tactile allodynia and showed diminished in potency against acute nociception without supraspinal/spinal antinociceptive synergy. Antiserum to dynorphin A((1-17)) or the non-competitive NMDA antagonist MK-801 increased the antinociceptive potency of i.th. morphine, restored supraspinal/spinal morphine antinociceptive synergy and elicited a dose-related i.th. morphine antiallodynic action. These agents did not demonstrate antinociceptive or antiallodynic activity alone and did not alter morphine actions in sham-operated animals. The loss of spinal/supraspinal antinociceptive synergy and lack of antiallodynic activity of spinal morphine appear to be due to the elevation across multiple spinal segments of dynorphin following nerve injury. Pathological actions of elevated dynorphin may directly or indirectly modulate the NMDA receptor, result in a loss of supraspinal/spinal morphine synergy and may thus account for the decreased clinical analgesic efficacy of morphine in peripheral neuropathies.
Department of Pharmacology, University of Arizona Health Sciences Center, Tucson, AZ 85724, USA.
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D
Bian
M H
MH
Ossipov
M
M
Ibrahim
R B
RB
Raffa
R J
RJ
Tallarida
T P
TP
Malan
J
J
Lai
F
F
Porreca
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004357:Drug Synergism; D004399:Dynorphins / Q000276:immunology*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use*; D007106:Immune Sera; D007276:Injections, Intraventricular; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009437:Neuralgia / Q000188:drug therapy*; D010147:Pain Measurement; D059348:Peripheral Nerve Injuries; D051381:Rats; D017207:Rats, Sprague-Dawley; D014110:Touch / Q000502:physiology
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D007106:Immune Sera; D016291:Dizocilpine Maleate; D004399:Dynorphins; D009020:Morphine