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.

Effect of testosterone on morphine withdrawal syndrome in rats.

AIM: To determine whether testosterone is involved in morphine withdrawal syndrome (WS). METHODS: In order to induce dependency, rats were treated with subcutaneous injection of morphine (days 1-2, 5 mg/kg; days 3-5, 7.5 mg/kg; days 6-8, 10 mg/kg), and after the last dose of morphine (day 8) WS was induced by intraperitoneal injection of naloxone (1 mg/kg). Wet dog shake (WDS), abdomen writhing (AW), and jumps (J) were recorded as indicators of WS. RESULTS: The severity of WDS, AW, and J in male rats was greater than that in females. Accordingly, in 4-week castrated and flutamide-treated (10 mg/kg/day for 8 days, i.p.) male rats, WDS, AW, and J were significantly decreased compared to male control rats. Testosterone replacement therapy (10 mg/kg/day for 8 days, i.m.) in 4-week castrated rats restored the severity of WDS, AW, and J behaviors to the level of non-castrated male rats, whereas testosterone potentiated the WDS behavior in non-castrated male rats. CONCLUSION: It can be concluded that testosterone might be effectively involved in morphine WS.

Role of 5-HT(1A) and 5-HT(2) receptors of dorsal and median raphe nucleus in tolerance to morphine analgesia in rats.

Several studies indicate that central serotonergic neurons have important role in morphine analgesia and tolerance. The aim of this study was to investigate possible role of 5-HT(1A) and 5-HT(2) receptors in dorsal and median raphe nucleus on development of tolerance to analgesic effect of morphine using hot plate test. Chronic injection of 5-HT(1A) receptor agonist 8-OH-DPAT (8-hydroxy-2-[di-n-propylamino]tetralin) (2, 4 and 8 mug/rat/day) to dorsal raphe nucleus (DRN) delayed tolerance to morphine analgesia, whereas injection of the same doses of 8-OH-DPAT to the median raphe nucleus (MRN) did not alter tolerance to morphine. In addition, chronic administration of ketanserin (1.5, 3 and 6 mug/rat/day), as a 5-HT(2) receptors antagonist, in DRN and MRN did not produce any significant effect. We conclude that 5-HT(1A) receptors of DRN are involved in tolerance to antinociceptive effect of morphine. However, the exact mechanism of interaction between serotonergic and opioidergic systems is not clear and remains to be elucidated.

Involvement of serotoninergic mechanism in analgesia by castration and flutamide, a testosterone antagonist, in the rat formalin test.

Several studies have suggested that testosterone has a role in nociception. Recently, we have shown that castration and flutamide, a testosterone antagonist, induce analgesia in the late phase of formalin test, which is related to increase of 5-HT levels in the dorsal horn of the lumbar spinal cord. The aim of the present study was to investigate the effect of fluoxetine, a selective serotonin reuptake inhibitor, on castration and flutamide-induced analgesia in order to further explore the role of 5-HT systems in such analgesia. Four weeks after castration, there was an analgesia in the late phase of formalin test, and this was potentiated by acute (0.32 mg kg(-1) ip) treatment of fluoxetine. Furthermore, coadministration of fluoxetine (0.32 mg kg(-1) ip) and flutamide (10 mg kg(-1) ip) produced more antinociceptive effect than those animals receiving fluoxetine and flutamide alone. The analgesic effect of fluoxetine (0.32 mg kg(-1) ip) and flutamide (10 mg kg(-1) ip) was abolished by pretreatment with 5,7-DHT (100 microg/rat it) and naloxone (2 mg kg(-1) ip). In summary, our data suggest that fluoxetine and flutamide have antinociceptive effects in tonic inflammatory pain through functional alteration of serotonergic systems, and their effects are potentiated by coadministration. The possible role of opioidergic system in their antinociceptive effect cannot be neglected.