Reduced effect of morphine in midbrain raphe lesioned rats

Self Cite

1 The effects of various narcotic analgesics on the uptake and release of labelled 5-hydroxytryptamine (5-HT) in brain and spinal cord synaptosomes were investigated.2 Methadone was most active in inhibiting 5-HT uptake (IC50 2.5 x 10-M). Levorphanol also inhibited 5-HT uptake to a large extent (IC5o 8.8 x 10-7 M) while dextrorphan, pethidine and pentazocine showed much less activity. Etorphine and morphine had virtually no such activity, with IC50s higher than 10-' and 1O-M respectively.3 The same order of potency as '5-HT releasers' was found when radioactivity was measured in [3H]-5-HT preloaded synaptosomal pellets incubated for 20min with the various narcotics. Methadone, like chlorimipramine, showed a significant effect at a concentration of 10-7M while morphine, at a concentration of 10-4 M, had no effect.4 When 5-HT release was studied by a perfusion technique, which largely prevents reuptake of the released amine, only fenfluramine, an anorectic agent proposed as a 5-HT releaser, significantly increased spontaneous 5-HT release. These data suggest that the apparent 5-HT release induced by various narcotics in traditional incubation techniques may largely depend on their ability to interfere with neurotransmitter reuptake mechanisms. 5 The effects of the various narcotics on 5-HT uptake have no relationship to their relative potency as analgesics in the rat. In the light of their poor effectiveness as 5-HT releasers, it can be concluded that mechanisms other than 5-HT uptake inhibition and release are probably involved in the analgesic effects of these compounds in intact animals.

Section: Introductionmentioning

confidence: 98%

Effects of Narcotic Analgesics on the Uptake and Release of 5‐hydroxytryptamine in Rat Synaptosomal Preparations

Mennini

Samanin

1978

Self Cite

“…Muscimol injections in the cerebral ventricles or in the periaqueductal grey that muscimol-sensitive sites in different brain regions influence the effect of morphine on tail-flick response in rats. As regards the lack of effect of muscimol injection in the MR, it has previously been shown that electrolytic lesions in this area reduce the effect of morphine on various nociceptive responses (Samanin et al, 1970;Garau, Mulas & Pepeu, 1975;Chance et al, 1978). These findings, however, did not provide clear-cut evidence that 5-HT neurones in MR were involved, although in one study 5-hydroxytryptophan, a precursor of 5-HT, was able to restore morphine activity in MR-lesioned animals (Samanin & Bernasconi, 1972).…”

Section: Discussionmentioning

confidence: 94%

“…Although muscimol-sensitive sites involved in morphine's effect on tail flick may exist in other brain areas, the nucleus raphd medianus, an area previously involved in the effect of morphine in various nociceptive responses (Samanin et al 1970 …”

Section: Discussionmentioning

confidence: 99%

“…Muscimol injections may therefore constitute a useful tool for investigating the role of 5-HT neurones in the raphe nuclei. Studies with electrical lesions and stimulation of either DR or MR in rats have suggested an involvement of the raphe nuclei in the antinociceptive effect of morphine (Samanin, Gumulka & Valzelli, 1970;Sasa, Munekiyo, Osumi & Takaori 1977;Chance, Krynock & Rosecrans, 1978), but it is not yet completely clear whether 5-HT neurones are implicated (Blasig, Reinhold & Herz, 1973;Buxbaum, Yarbrough & Carter, 1973). Much more attention has been recently paid to the possible role of 5-HT neurones originating in the nucleus raphe magnus in morphine analgesia in rats (Proudfit & Anderson, 1975;Mohrland & Gebhart, 1980).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Muscimol injections in the nucleus raphé dorsalis block the antinociceptive effect of morphine in rats: apparent lack of 5‐hydroxytryptamine involvement in muscimol's effect

Romandini

Samanin

1984

1The 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 raphe dorsalis (DR) or medianus (MR). 2 The levels of 5-hydroxyindoleacetic acid (5-HIAA) were measured in the hippocampus and striatum of muscimol-injected animals. 3Muscimol 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. 4 Muscimol injections in the DR blocked the effect of morphine while no effect was seen in animals which had received muscimol in the MR.5 An injection of 5,7-dihydroxytryptamine (6 tig in 3 pl) in the DR did not change the effect of morphine or muscimol. 6 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.

“…For example, electrolytic destruction of the midbrain raphe nuclei (Samanin, Gumulka & Valzelli, 1970;Yaksh, Plant & Rudy, 1977) and nucleus raphe magnus (Proudfit & Anderson, 19751 as well as p-chlorophenylalanine administration (Tenen, 1968) have been shown to attenuate morphine-induced antinociception. Further, it has been reported that the selective inhibition of 5-HT reuptake by fluoxetine produces hypoalgesia and potentiates morphineinduced antinociception (Sugrue & Mclndewar, 1976;Messing, Phebus, Fisher & Lytle, 1975).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of Pethidine‐induced Antinociception by Zimelidine, an Inhibitor of 5‐hydroxytryptamine Reuptake

Gebhart

Lorens

1980

1 The effect of selective inhibition of 5-hydroxytryptamine (5-HT) re-uptake by fluoxetine and zimelidine on morphine-and pethidine-induced antinociception was studied in rats. The hot plate (55°C) and tail flick test procedures for measurement of analgesia were employed to assess antinociception. 2 Pretreatment with fluoxetine and zimelidine potentiated the antinociceptive effect of morphine (4.5 mg/kg, as base); zimelidine was without effect on a lesser dose of morphine (3.0 mg/kg, as base). 3 Pretreatment with zimelidine but not fluoxetine, significantly attenuated pethidine-induced antinociception (24 mg/kg, as base) and prevented the expression of pethidine-induced antinociception at a lesser 10 mg/kg (as base) dose of pethidine. 4 These and other results support (a) a role for 5-HT in the expression of morphine-induced antinociception, and (b) a different mode of antinociceptive action of morphine and pethidine. The role of 5-HT in pethidine-induced antinociception remains unclear.