8-OH-DPAT prevents morphine-induced apoptosis in rat dorsal raphe nucleus: a possible mechanism for attenuating morphine tolerance.

Background: Previously, we found that activation of serotonin 1A (5-HT1A) receptors in the dorsal raphe nucleus (DRN) decreased the development of tolerance to the analgesic effect of morphine. It has been indicated that tolerance to the analgesic effect of morphine is associated with apoptosis in the central nervous system. In this investigation we attempted to evaluate the effect of 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino]tetralin), a specific 5-HT1A receptor agonist, on morphine-induced tolerance and apoptosis in rat DRN.

Methods: Nociception was assessed using a hotplate apparatus. The terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) method was used to analyze apoptosis.

Results: Tolerance to the analgesic effect of morphine was complete by 10 days after morphine administration (5 mg/kg/d, i.p.), whereas a significant analgesic effect was observed through the 10th day in 8-OH-DPAT-treated animals. Furthermore, the results showed that the number of TUNEL positive cells had been increased in morphine-tolerant rats (control group: morphine, i.p. + saline, intra-DRN) in comparison with the saline-treated animals. The results also indicated that 8-OH-DPAT (2, 4, and 8 μg/rat/d) attenuated the number of apoptotic cells in the DRN in comparison with the control group. However, 8-OH-DPAT (8 μg/rat/d, intra-DRN) failed to reduce morphine-induced apoptosis in the presence of the 5-HT1A receptor antagonist, NAN-190 (6 μg/rat/d, intra-DRN).

Conclusion: We found that intra-DRN injection of a specific 5-HT1A receptor agonist attenuated morphine-induced apoptosis in rat DRN, which may have a key role in morphine tolerance.