The role of the nucleus raphe pontis and the caudate nucleus in alfentanil rigidity in the rat

Blasco, T. A.; Lee, D.; Amalric, Marianne; Swerdlow, Neal R.; Smith, N. Ty; Koob, George F.

doi:10.1016/0006-8993(86)90164-2

Cited by 29 publications

(15 citation statements)

References 34 publications

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“…administration of high doses of fentanyl and alfentanil produces skeletal muscle rigidity resulting in stiffness of the chest wall (Benthuysen et al, 1986;Streisand et al, 1993;Waller, Hug, Nagle, & Craver, 1981). Brain microinjection studies in rats have implicated several brain regions-locus coeruleus, basal ganglia, nucleus raphe pontis, and periaqueductal grey-as sites of action of fentanyls to induce muscle rigidity (Blasco et al, 1986;Lui, Lee, & Chan, 1989;Lui, Lee, & Chan, 1990;Slater & Starkie, 1987;Weinger et al, 1991;Widdowson, Griffiths, & Slater, 1986) and have shown that it is mediated by activation of μ, and not δ or κ opioid receptors (Vankova et al, 1996). It is likely therefore that in humans, i.v.…”

Section: Discussionmentioning

confidence: 99%

Fentanyl depression of respiration: Comparison with heroin and morphine

Hill

Santhakumar

Dewey

et al. 2019

British J Pharmacology

139

119

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Background and Purpose: Fentanyl overdose deaths have reached "epidemic" levels in North America. Death in opioid overdose invariably results from respiratory depression. In the present work, we have characterized how fentanyl depresses respiration, and by comparing fentanyl with heroin and morphine, the active breakdown product of heroin, we have sought to determine the factors, in addition to high potency, that contribute to the lethality of fentanyl.Experimental Approach: Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole body plethysmography.Key Results: Intravenously administered fentanyl produced more rapid depression of respiration than equipotent doses of heroin or morphine. Fentanyl depressed both respiratory rate and tidal volume. Fentanyl did not depress respiration in μ-opioid receptor knockout mice. Naloxone, the opioid antagonist widely used to treat opioid overdose, reversed the depression of respiration by morphine more readily than that by fentanyl, whereas diprenorphine, a more lipophilic antagonist, was equipotent in reversing fentanyl and morphine depression of respiration. Prolonged treatment with morphine induced tolerance to respiratory depression, but the degree of cross tolerance to fentanyl was less than the tolerance to morphine itself. Conclusion and Implications:We propose that several factors (potency, rate of onset, lowered sensitivity to naloxone, and lowered cross tolerance to heroin) combine to make fentanyl more likely to cause opioid overdose deaths than other commonly abused opioids. Lipophilic antagonists such as diprenorphine may be better antidotes than naloxone to treat fentanyl overdose.

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Section: Discussionmentioning

confidence: 99%

Fentanyl depression of respiration: Comparison with heroin and morphine

Hill

Santhakumar

Dewey

et al. 2019

British J Pharmacology

139

119

View full text Add to dashboard Cite

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“…They induce a catatonic immobilization by acting on localized areas in the central nervous system (41). In the rat, at least, the most prominent of these areas are the nucleus raphe pontis (1,5,6,41,44) and the nucleus accumbens (12). Both these nuclei contain serotonergic receptors (44), and serotonin enhances opioid-induced catatonia (6,12,44).…”

Section: Discussionmentioning

confidence: 99%

Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats

Meyer

Fuller

Mitchell

2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Neurophysiological studies have shown that serotonergic ligands that bind to 5-HT1A, 5-HT7, and 5-HT4 serotonin receptors in brain stem have beneficial effects on respiratory neurons during opioid-induced respiratory depression. The effect of these ligands on respiratory function and pulmonary performance has not been studied. We therefore examined the effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an agonist of 5-HT1A and 5-HT7 receptors, and zacopride, an agonist of 5-HT4 receptors, to establish whether these ligands would reverse opioid-induced respiratory depression and hypoxia without affecting the immobilizing properties of the opioid drug etorphine. When etorphine was used to sedate and immobilize goats, it significantly decreased respiratory rate (P = 0.013), percent hemoglobin oxygen saturation (P < 0.0001), and arterial oxygen partial pressure [Pa(O2); F(10,70) = 5.67, P < 0.05] and increased arterial carbon dioxide partial pressure [F(10,70) = 3.87, P < 0.05] and alveolar-arterial oxygen partial pressure gradient [A-a gradients; F(10,70) = 8.23, P < 0.0001]. Zacopride and 8-OH-DPAT, coadministered with etorphine, both attenuated the effects of etorphine; respiration rates did not decrease, and percent hemoglobin oxygen saturation and Pa(O2) remained elevated. Zacopride decreased the hypercapnia, indicating an improvement in ventilation, whereas 8-OH-DPAT did not affect the hypercapnia and, therefore, did not improve ventilation. The main beneficial effect of 8-OH-DPAT was on the pulmonary circulation; it improved oxygen diffusion, indicated by the normal A-a gradients, presumably by improving ventilation perfusion ratios. Neither zacopride nor 8-OH-DPAT reversed etorphine-induced catatonic immobilization. We conclude that serotonergic drugs that act on 5-HT1A, 5-HT7, and 5-HT4 receptors reverse opioid-induced respiratory depression and hypoxia without reversing catatonic immobilization.

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“…In man, intravenous administration of fentanyl and alfentanil produces skeletal muscle rigidity resulting in stiffness of the chest wall (Benthuysen et al, 1986;Streisand et al, 1993;Waller et al, 1981). Brain micro injection studies in rats have implicated several brain regions -locus coeruleus, basal ganglia, nucleus raphe pontis and periaqueductal grey -as sites of action of fentanyls to induce muscle rigidity (Blasco et al, 1986;Lui et al, 1989;Lui et al, 1990;Slater et al, 1987;Weinger et al, 1991;Widdowson et al, 1986) and have shown that it is mediated by activation of , and not  or  opioid receptors (Vankova et al, 1996). It is likely therefore that in man intravenous injection of fentanyl results in both a decreased drive to breathe and a mechanical resistance to breathing both of which would contribute to overdose death (Burns et al, 2016).…”

mentioning

confidence: 99%

Fentanyl depression of respiration: comparison with heroin and morphine

Hill

Santhakumar

Dewey

et al. 2019

Preprint

View full text Add to dashboard Cite

Background and Purpose:Fentanyl overdose deaths have reached 'epidemic' levels in North America. Death in opioid overdose invariably results from respiratory depression. In the present work we have characterized how fentanyl depresses respiration and by comparing fentanyl with heroin and morphine, the active breakdown product of heroin, we have sought to determine whether there are factors, in addition to high potency, that contribute to the lethality of fentanyl. Experimental Approach:Respiration (rate and tidal volume) was measured in awake, freely moving mice by whole body plethysmography Key ResultsIntravenously administered fentanyl produced more rapid depression of respiration than equipotent doses of heroin or morphine. Fentanyl depressed both respiratory rate and tidal volume, the effect on tidal volume may reflect increased respiratory muscle stiffness. Fentanyl did not depress respiration in  opioid receptor knock-out mice. Naloxone, the opioid antagonist widely used to treat opioid overdose, reversed the depression of respiration by morphine more readily than that by fentanyl whereas diprenorphine, a more lipophilic antagonist, was equipotent in reversing fentanyl and morphine depression of respiration. Prolonged treatment with morphine induced tolerance to respiratory depression but the degree of cross tolerance to fentanyl was less than the tolerance to morphine itself. Conclusion and Implications:We propose that several factors (potency, rate of onset, muscle stiffness, lowered sensitivity to naloxone and lowered cross tolerance to morphine) combine to make

show abstract

The role of the nucleus raphe pontis and the caudate nucleus in alfentanil rigidity in the rat

Cited by 29 publications

References 34 publications

Fentanyl depression of respiration: Comparison with heroin and morphine

Fentanyl depression of respiration: Comparison with heroin and morphine

Zacopride and 8-OH-DPAT reverse opioid-induced respiratory depression and hypoxia but not catatonic immobilization in goats

Fentanyl depression of respiration: comparison with heroin and morphine

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