Search

A single subcutaneous injection of 5 mg/kg metergoline or 10 mg/kg methysergide, two serotonin antagonists, or 1 mg/kg naloxone, significantly reduced the effect of a subcutaneous dose of 3 mg/kg morphine in the tail immersion test in rats. The same drugs and doses were administered concurrently with 10 mg/kg morphine twice daily for 3 days and nociceptive responses were measured 96 h later. Tolerance to the effect of 3 mg/kg morphine was comparable in animals which had received vehicle + morphine or serotonin antagonists + morphine, whereas naloxone completely prevented the development of tolerance. The results argue against a role of serotonin in the development of tolerance to the antinociceptive effect of morphine and suggest it may be possible to dissociate morphine analgesia from tolerance development, at least in the conditions used in the present study.

The regional brain metabolism of serotonin (5-HT) and dopamine (DA) was studied in rats injected with morphine either systemically or in the nuclei raphe medianus (MR) or dorsalis (DR). A subcutaneous injection of 10 mg/kg morphine significantly raised the levels of 5-hydroxyindoleacetic acid (5-HIAA) in the diencephalon, striatum, nucleus accumbens and cortex with no effect in the hippocampus. Similar changes in 5-HT metabolism were found in animals injected with 5 micrograms/0.5 microliter in the DR whereas morphine injected in the MR raised 5-HIAA levels only in the nucleus accumbens. A subcutaneous or direct injection of morphine in the DR significantly raised the levels of homovanillic acid (HVA) and dihydroxyphenylacetic acid (DOPAC) in the striatum and nucleus accumbens, but injection in the MR was ineffective. All the effects of morphine were blocked by naloxone, injected either intraperitoneally (1 mg/kg) or directly in the raphe nuclei (2 micrograms/0.5 microliter). Pretreatment with parachlorophenylalanine, an inhibitor of serotonin synthesis, significantly reduced the effect of morphine injected in the DR on dopamine metabolism in the striatum and nucleus accumbens. The data suggest that a major mechanism by which morphine increases 5-HT metabolism in the rat forebrain is activation of 5-HT cells in the nucleus raphe dorsalis, and this action may contribute to the increased DA metabolism found in the animal injected with morphine in this brain area.

The effect of different manipulations of the nucleus medianus raphe (MR) on morphine analgesia was investigated in rats using the tail-immersion test. Electrolytic lesions of this structure antagonized morphine analgesia, while injections of 5,7-dihydroxytryptamine (to destroy serotonergic neurons) or ibotenic acid (to destroy cell bodies) in the medianus raphe did not alter the effect of morphine. Injection of naloxone (0.5 and 0.1 micrograms) in the MR antagonized morphine analgesia. These results suggest the importance of this structure for morphine analgesia in this test, although the substrates within the nucleus that mediate this action are still unknown.

The possibility that serotoninergic mechanisms control the reinforcing properties of d-amphetamine and morphine was investigated in rats, using zimelidine, a potent and selective serotonin uptake blocker and the conditioned place preference test design. Zimelidine dihydrochloride 20 mg/kg did not cause place aversion and did not modify the place preference induced by 5 mg/kg morphine hydrochloride. Place preference induced by 5 mg/kg d-amphetamine sulphate was completely blocked by pretreatment with zimelidine. The results suggest that the reinforcing properties of d-amphetamine, but not of opioid agonists, may be reduced by agents which increase serotonin transmission in the brain.

The effects of d-fenfluramine and morphine on various nociceptive responses of rats were investigated. Unlike morphine, which inhibited all the responses examined, d-fenfluramine inhibited jumping and paw licking of rats on a hot plate, but did not increase the latency of tail withdrawal from hot water. The effects of d-fenfluramine on both responses on the hot plate were prevented by pretreatment with metergoline, a serotonin antagonist, whereas this pretreatment only reduced the effect of morphine on paw licking. The inhibition of tail withdrawal by morphine was also significantly reduced by metergoline treatment. The results confirm previous findings suggesting a role of serotonin in the mechanism by which morphine inhibits some nociceptive responses in rats. They also show that d-fenfluramine, a selective releaser and uptake inhibitor of serotonin at nerve endings, does not completely reproduce the antinociceptive effects of morphine in this species.

5,7-Dihydroxytryptamine (5,7-DHT) injections in the ventromedial tegmentum (VMT) at the level of nucleus interpeduncularis or in the ventral raphe area (VR) of the medulla oblongata were used to study the separate roles of forebrain and spinal 5-HT in the antinociceptive effect of morphine in rats. 5,7-DHT injections in the VMT, which caused marked, selective depletion of forebrain 5-HT, did not modify the effect of morphine in the hot plate and tail immersion tests. Direct injection of 5,7-DHT into the nucleus raphe medianus also failed to modify the effect of morphine in the two tests used to measure nociceptive responses. The effect of morphine was significantly reduced 30 min after injection to rats depleted of spinal 5-HT by 5,7-DHT injected in the VR but the areas under the curves between vehicle and 5,7-DHT treated animals were not significantly different. The data show that the integrity of 5-HT neurons in the forebrain is not necessary for the antinociceptive effect of morphine and a substantial amount of this effect is still present in rats with marked depletion of spinal 5-HT.

(+)-Fenfluramine, a 5-hydroxytryptamine (5-HT) releaser and uptake blocker, m-chlorophenylpiperazine (CPP), a 5-HT receptor agonist, and clonidine, an agonist at adrenoceptors, were studied for their ability to modify jumping and wet dog shakes in morphine abstinent rats. (+)-Fenfluramine and CPP blocked jumping with no effect on wet dog shakes whereas the reverse was true for clonidine. The results further show that 5-HT mechanisms are preferentially involved in the expression of jumping in morphine-abstinent rats.

The analgesic effect of morphine in the tail immersion test was studied in rats three and ten days after intracerebroventricular 5,7-dihydroxytryptamine (5,7-DHT) given to selectively destroy serotonergic neurons. Morphine analgesia was reduced three but not ten days after the neurotoxin. Ten days after 5,7-DHT, the inhibiting effect of metergoline, a serotonin antagonist, on morphine analgesia was still present, suggesting that functional recovery of the serotonergic system may partly explain the different results.

The effect of morphine (3 mg kg-1 subcutaneously) on tail flick in the tail immersion test was studied in rats which had received a muscimol (100 ng) injection either in the nucleus raphé dorsalis (DR) or medianus (MR). The levels of 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus and striatum of muscimol-injected animals. Muscimol injections in the DR reduced 5-HIAA concentrations in the striatum but not in hippocampus, whereas in animals which had received muscimol in the MR a selective decrease in hippocampal 5-HIAA levels was found. Muscimol injections in the DR blocked the effect of morphine while no effect was seen in animals which had received muscimol in the MR. An injection of 5,7-dihydroxytryptamine (6 micrograms in 3 microliter) in the DR did not change the effect of morphine or muscimol. These findings indicate that muscimol-sensitive neurones in the DR, which are probably not 5-hydroxytryptaminergic, are involved in the effect of morphine on tail flick in tail immersion. The muscimol-sensitive neurones involved in this effect of morphine do not seem to exist in the MR.