Baclofen and Morphine antinociception tolerance: Interaction between the GABAergic and opioid systems

BALERIO GRACIELA N., KEMMLING ALMA K., RUBIO MODESTO C.

Los Angeles, USA

Simposio; 4th International GABAB Symposium; 1998

Baclofen and Morphine antinociception tolerance: Interaction between the GABAergic and opioid systems Graciela N Balerio, Alma K Kemmling, Modesto C Rubio, Cátedra. de Farmacología e ININFA (CONICET), Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956, 5º Piso, 1113, Buenos Aires, Argentina. Several studies have found a role of GABA in opiate dependence and antinociception. Morphine (MOR), a selective opioid agonist, develops dependence and tolerance to several effects after a chronic administration. In previous studies we have demonstrated a possible interaction between the GABAergic and opiodergic systems involved in baclofen (BAC) antinociceptive effect (1). We assayed a selective GABA B agonist (BAC), alone and in combination with MOR, studying the development of tolerance to the antinociceptive effect. All the experiments were performed on male Swiss-Webster albino mice (25-40 g) and the nociceptive latencies were determined at 60 min after drug administration. Mice were administered with MOR 2 mg/kg  i.p., twice daily for 8 days and the maximum possible effect (MPE) was determined by hot plate test (2). This chronic MOR treatment reduced the antinociceptive effect by 62 %, n=9, p< 0.001 compared with the acute group of MOR, n=8. Another group of mice were injected with BAC 2 mg/kg i.p. twice a day for 8 days and the MPE was reduced by 89 %, n=10, p< 0.001 compared with the acute group of BAC, n=10. In another group of animals, after a chronic MOR treatment, BAC 2 mg/kg was administered as the last dose on the test day and the antinociceptive effect was reduced by 65%, n=11, p< 0.001 compared with the acute group of BAC, n=11. Besides, we tested a chronic BAC administration for 8 days and MOR was administered as the last dose on the test day and the antinociceptive effect was reduced by 56 %, n=10, p< 0.001 compared with the acute group of MOR, n=11. In conclusion, we have observed the development of tolerance to the antinociceptive effect of the two agonists (BAC and MOR) and the development of cross-tolerance between both drugs. These results suggest a possible interaction between the GABAergic and opioid systems.         References 1.       Balerio GN, Doctoral Thesis, Facultad de Farmacia y Bioquímica, UBA, 1996. 2.       Eddy NB and Leimbach DJ, J Pharmacol Exp Ther, 107: 385-393, 1953.