Fentanyl and sufentanil inhibit agonist binding to 5-HT1A receptors in membranes from the rat brain

Martin, D.C.; Introna, Robert P. S.; Aronstam, Robert S.

doi:10.1016/0028-3908(91)90056-h

Cited by 20 publications

(15 citation statements)

References 14 publications

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“…However, fentanyl and oxycodone were also linked to serotonin syndrome but did not interact with the SERT in vitro , suggesting SERT‐independent effects on the 5‐HT system in vivo . Therefore, some opioids may also directly interact with 5‐HT receptors, such as 5‐HT 1A and 5‐HT 2A , that have been implicated in animal models of serotonin syndrome (Martin et al, ; Van Oekelen et al, ; Tao et al, ; Fox et al, ), or indirectly activate 5‐HT release via opioid receptor stimulation (Tao and Auerbach, ; Tao and Auerbach, ; Benade et al, ). In fact, the present study showed that fentanyl directly bound to 5‐HT 1A , as previously shown (Martin et al, ) and, also to 5‐HT 2A receptors, although both at concentrations clearly higher than those observed in human plasma.…”

Section: Discussionmentioning

confidence: 99%

“…We also tested whether opioids that interact with one of these monoamine transporters induce transporter‐mediated monoamine release. Furthermore, activity at 5‐HT 1A , 5‐HT 2A and 5‐HT 2C receptors may be involved in animal models of the serotonin syndrome (Martin et al, ; Van Oekelen et al, ; Tao et al, ; Fox et al, ). Therefore, we determined the affinities of opioids to bind directly to these 5‐HT receptors.…”

Section: Introductionmentioning

confidence: 99%

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Opioid‐induced inhibition of the human 5‐HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome

Rickli

Liakoni

Hoener

et al. 2018

British J Pharmacology

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Background and PurposeOpioids may inhibit the 5‐HT transporter (SERT) and the noradrenaline transporter (NET). NET inhibition may contribute to analgesia, and SERT inhibition or interactions with 5‐HT receptors may cause serotonergic toxicity. However, the effects of different opioids on the human SERT, NET and 5‐HT receptors have not been sufficiently studied.Experimental ApproachWe determined the potencies of different opioids to inhibit the SERT and NET in vitro using human transporter‐transfected HEK293 cells. We also tested binding affinities at 5‐HT1A, 5‐HT2A and 5‐HT2C receptors. Additionally, we assessed clinical cases of the serotonin syndrome associated with each opioid reported by PubMed and a World Health Organization database.Key ResultsDextromethorphan, l(R)‐methadone, racemic methadone, pethidine, tramadol and tapentadol inhibited the SERT at or close to observed drug plasma or estimated brain concentrations in patients. Tapentadol was the most potent NET inhibitor. Pethidine, tramadol, l(R)‐methadone, racemic methadone, dextromethorphan and O‐desmethyltramadol also inhibited the NET. 6‐Monoacetylmorphine, buprenorphine, codeine, dihydrocodeine, heroin, hydrocodone, hydromorphone, morphine, oxycodone and oxymorphone did not inhibit the SERT or NET. Fentanyl interacted with 5‐HT1A receptors and methadone, pethidine and fentanyl with 5‐HT2A receptors, in the low micromolar range. Opioids most frequently associated with the serotonin syndrome are tramadol, fentanyl, tapentadol, oxycodone, methadone and dextromethorphan.Conclusions and ImplicationsSome synthetic opioids interact with the SERT and NET at potentially clinically relevant concentrations. SERT inhibition by tramadol, tapentadol, methadone, dextromethorphan and pethidine may contribute to the serotonin syndrome. Direct effects on 5‐HT1A and/or 5‐HT2A receptors could be involved with methadone and pethidine.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Opioid‐induced inhibition of the human 5‐HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome

Rickli

Liakoni

Hoener

et al. 2018

British J Pharmacology

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“…Because of its affinity for the 5-HT 1A receptor, it also influences 5-HT efflux [6,7]. Tao et al [8] reported that systemic injection of fentanyl 0.01 to 0.2 mg/kg subcutaneously acts as a 5-HT 1A agonist in vivo.…”

Section: Discussionmentioning

confidence: 97%

A possible perianesthetic serotonin syndrome related to intrathecal fentanyl

Özkardeşler

Gürpınar

Akan

et al. 2008

Journal of Clinical Anesthesia

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“…However, this conclusion remains tentative for three reasons. First, fentanyl binds to 5‐HT 1A receptors as well as to opioid receptors (Martin et al . 1991).…”

Section: Regional Site Of Action Of Morphinementioning

confidence: 99%

Systemic morphine‐induced release of serotonin in the rostroventral medulla is not mimicked by morphine microinjection into the periaqueductal gray

Taylor¹,

Basbaum

2003

Journal of Neurochemistry

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We used in vivo microdialysis in awake rats to test the hypothesis that intravenous morphine increases serotonin (5-HT) release within the rostral ventromedial medulla (RVM). We also injected morphine into various sites along the rostrocaudal extent of the periaqueductal gray (PAG), and examined the extent of its diffusion to the RVM. Intravenous morphine (3.0 mg/kg) produced thermal antinociception and increased RVM dialysate 5-HT, 5-hydroxyindole acetic acid (5-HIAA), and homovanillic acid (HVA) in a naloxone-reversible manner. As neither PAG microinjection of morphine (5 lg/ 0.5 lL) nor RVM administration of fentanyl or D-Ala(2),NMePhe(4),Gly-ol(5)]enkephalin (DAMGO) increased RVM 5-HT, we were unable to determine the precise site of action of morphine. Surprisingly, peak morphine levels in the RVM were higher after microinjection into the caudal PAG as compared to either intravenous injection or microinjection into more rostral sites within the PAG. Naloxone-precipitated withdrawal in morphine-tolerant rats not only increased extracellular 5-HT in the RVM, but also dopamine (DA) and HVA. We conclude that substantial amounts of morphine diffuse from the PAG to the RVM, and speculate that opioid receptor interactions at multiple brain sites mediate the analgesic effects of PAG morphine. Further studies will be required to elucidate the contribution of 5-HT and DA release in the RVM to opioid analgesia and opioid withdrawal.

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Fentanyl and sufentanil inhibit agonist binding to 5-HT1A receptors in membranes from the rat brain

Cited by 20 publications

References 14 publications

Opioid‐induced inhibition of the human 5‐HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome

Opioid‐induced inhibition of the human 5‐HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome

A possible perianesthetic serotonin syndrome related to intrathecal fentanyl

Systemic morphine‐induced release of serotonin in the rostroventral medulla is not mimicked by morphine microinjection into the periaqueductal gray

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