FR-64822

This study was designed to investigate the effect of morphine on formalin-induced nociceptive responses in streptozotocin (STZ) induced-diabetic mice, noninsulin-dependent genetically diabetic db/db mice and their respective controls (ddY and (+/+)). In nondiabetic (ddY and (+/+)) mice, morphine (1-10 mg/kg, PO) dose dependently attenuated the biphasic nociceptive responses induced by s.c. injection of formalin to the hindpaw, demonstrating equipotency on both the first and second phases. Para-chlorophenylalanine (800 mg/kg x 2, PO) and pindolol (1 mg/kg, i.p.) reduced the effect of morphine on the first phase, sulpiride (10 mg/kg, i.p.) abolished the effect on both phases, while ketanserin (1 mg/kg, i.p.) had no effect. In STZ (200 mg/kg, i.p.)-diabetic mice, morphine weakly attenuated the nociception in comparison to control ddY mice, whereas it had comparable effects in both the first and second phases of control (+/+) mice and db/db mice. The serotonergic agonist, meta-chlorophenylpiperazine (0.32-3.2 mg/kg, PO), dose dependently attenuated the biphasic nociceptive responses to formalin in both phases of diabetic mice; however, FR64822, a dopaminergic compound (0.1-10 mg/kg, PO), had little effect. We speculate that activation of both dopaminergic (DA)- and serotonergic-mediated mechanisms are potentially responsible for the effect of morphine on the first phase, while the DA-mediated effect is involved in the second phase. The DA-mediated mechanism, but not the serotonin-mediated one, appears to be altered in both STZ-diabetic and db/db mice. These results suggest that the attenuated effects of morphine might be due to a dopaminergic dysfunction in STZ mice, and that there might be other mechanisms compensating for this attenuation of dopaminergic function in db/db mice.