Interaction between intrathecal morphine and glutamate receptor antagonists in formalin test.
The analgesic interaction between intrathecally administered morphine and the NMDA receptor antagonist, ((+/-)-2-amino-5-phosphonopentanoic acid; AP-5), the NMDA receptor glycine site antagonist, (5-nitro-6,7-dichloro-2,3-quinoxaline dion; ACEA 1021), or the AMPA (alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor antagonist (ACEA 2752) in the formalin test was investigated with a rat model of chronic lumbar intrathecal catheterization. After obtaining dose-response curves for each agent, combinations of morphine and AP-5, ACEA 1021 or ACEA 2752 were tested for their effect on the number of flinches in the formalin test and for associated side-effects, such as motor disturbances, flaccidity, and agitation/allodynia. Using isobolographic analyses, a potent analgesic synergy was observed with decreased side-effects between morphine and ACEA 2752 or AP-5. ACEA 1021 increased the analgesic effect of low-dose morphine. Spinal mu-opioid receptor activation and NMDA or AMPA receptor antagonism showed a synergistic antinociception against tonic pain. These results suggest an important direction in the management of inflammatory pain.
Nishiyama
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Department of Anesthesiology, The University of Tokyo, Japan. nishiyamat-ane@h.u-tokyo.ac.jp
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005557:Formaldehyde / Q000008:administration & dosage; D007278:Injections, Spinal; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000139:chemically induced / Q000517:prevention & control; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000187:drug effects; D017470:Receptors, Glutamate / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects
D000701:Analgesics, Opioid; D018691:Excitatory Amino Acid Antagonists; D011810:Quinoxalines; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; D005557:Formaldehyde; C092062:licostinel; D015763:2-Amino-5-phosphonovalerate; D009020:Morphine