Increased Extracellular Serotonin in Rat Brain After Systemic or Intraraphe Administration of Morphine

Abstract

The effect of morphine on serotonin (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) in the CNS of unanesthetized rats was investigated by microdialysis. Morphine was administered either subcutaneously, by local perfusion into the diencephalon, or by intraraphe microinjection. Systemic administration of morphine resulted in a significant increase in both extracellular 5‐HT and 5‐HIAA in the diencephalon. The effect of morphine on 5‐HT was dose dependent during local perfusion of the diencephalon with inhibitors of uptake or monoamine oxidase. Systemic morphine also produced significant increases in extracellular 5‐HT in the striatum and hippocampus during uptake inhibition. The site of opioid effects on 5‐HT was tested by locally perfusing morphine into the diencephalon. This had no effect on 5‐HT or 5‐HIAA. In contrast, intraraphe injection of morphine caused a dose‐dependent increase in extracellular 5‐HT and 5‐HIAA in the diencephalon. These results suggest that systemic morphine induces an increase in 5‐HT release in widespread areas of the forebrain. This appears to be due to an effect on 5‐HT cell bodies and not on 5‐HT nerve endings in projection sites.

Stressor Controllability Modulates Stress-Induced Dopamine and Serotonin Efflux and Morphine-Induced Serotonin Efflux in the Medial Prefrontal Cortex

“…Opioids acting on m receptors inhibit these GABA interneurons (Wang and Nakai, 1993), resulting in a disinhibition of 5-HT neurons in the DRN. Consistent with an action of morphine on DRN 5-HT neurons, increases in extracellular 5-HT have been observed in projection regions of the DRN after systemic or intra-raphe injections of morphine (Tao and Auerbach, 1994). If IS results in a downregulation of 5HT1 a autoreceptors, then activation of DRN 5-HT neurons by morphine in subjects that have been exposed to IS should result in a potentiated 5-HT response.…”

“…Morphine is known to activate DRN serotonergic neurons, but has only been shown to increase 5-HT efflux in the mPFC at high doses. 5-HT efflux increases significantly after doses of 10 and 20 mg/kg, but not after 5 mg/kg (Tao and Auerbach, 1994). It is interesting to note that in the Tao and Auerbach study, 5-HT levels peaked at 90 min.…”

“…Will et al (1998Will et al ( , 2002 suggested that these results might have been a product of the interaction between the sensitization of DRN neurons selectively produced by IS and dopaminergic (DA) processes in either the nucleus accumbens (NAc) or the medial prefrontal cortex (mPFC). Serotonin in these structures can potentiate DA release (Rasmusson et al, 1994), and it is noteworthy that morphine activates DRN 5-HT neurons (Tao and Auerbach, 1994) but amphetamine does not (Rebec and Curtis, 1983). Given that IS sensitizes DRN 5-HT neurons, morphine might be expected to produce exaggerated extracellular levels of 5-HT in projection regions of the DRN such as the mPFC in subjects that had been previously exposed to IS, thereby potentiating DA levels in them and thus potentiating reward-related processes.…”

Augmented Accumbal Serotonin Levels Decrease the Preference for a Morphine Associated Environment During Withdrawal

“…Acute morphine also enhances the turnover and release of 5-HT and dopamine (DA) in widespread areas of the forebrain (Spampinato et al 1985;Tao and Auerbach 1994). The effect of morphine on 5-HT release appears to be mediated by activation of dorsal raphe neurons (Spampinato et al 1985;Tao and Auerbach 1994) and may reflect disinhibition caused by direct inhibition of GABA transmission. A similar mechanism has also been proposed for the excitatory effects of opiates on DA neurons in the ventral tegmental area (Bloom et al 1972;Bonci and Williams 1997).…”

The pathophysiological role of serotonin receptor systems in opioid analgesia and tolerance

“…106 Systemic administration of morphine causes the release of 5-HT in different brainstem locations and the spinal cord dorsal horn. 21,107 Though the mechanism of morphine stimulated the 5-HT release remains obscure, it has been shown the involvement of excitatory neurotransmitter and GABA. 100,106 Furthermore, 5-HT 1A and 5-HT 1B receptors are involved in regulation spinal pain transmission, and morphine analgesia could be inhibited by administration of either mianserin (a 5-HT 1C antagonist) or spiperone (a 5-HT 1A antagonist).…”