licostinel and Pain

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.

Topics: 2-Amino-5-phosphonovalerate; Analgesics, Opioid; Animals; Behavior, Animal; Dose-Response Relationship, Drug; Drug Interactions; Excitatory Amino Acid Antagonists; Formaldehyde; Injections, Spinal; Male; Morphine; Motor Activity; Pain; Quinoxalines; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate

Intrathecal administration of N-methyl-D-aspartate (NMDA) and non-NMDA receptor antagonists has been shown to produce antinociception in various animal models of pain. In the present study we examined the effect of 5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (ACEA-1021), a competitive NMDA receptor/glycine site antagonist, on nociceptive responses in the tail flick and formalin tests in mice. Swiss Webster mice were injected with ACEA-1021 intraperitoneally (1-60 mg/kg), or intrathecally (1-40 micrograms/mouse), and tested for antinociception. Systemic administration of ACEA-1021 attenuated the nociceptive responses solely in the formalin test. Nevertheless, intrathecal administration of ACEA-1021 showed equally potent attenuation of nociceptive responses in both animal models of pain. The effect of ACEA-1021 was also examined on caudally directed biting and scratching (CDBS) behaviors induced by intrathecal administration of NMDA. Microinjections of NMDA (1-1000 microM) in the spinal cord produced dose-dependent CDBS behaviors. Mice pretreated with ACEA-1021 (0.5-40 micrograms/mouse) showed dose-dependent protection against CDBS behaviors induced by intrathecal NMDA. Taken together, the results suggest that ACEA-1021 may block spinal NMDA receptors to attenuate nociceptive responses, however, our data cannot exclude the involvement of non-NMDA receptors.

Topics: Animals; Behavior, Animal; Excitatory Amino Acid Antagonists; Injections, Intraperitoneal; Injections, Spinal; Male; Mice; Mice, Inbred Strains; Microinjections; Pain; Pain Measurement; Quinoxalines; Receptors, Glycine; Receptors, N-Methyl-D-Aspartate