Brain sites mediating opiate-induced muscle rigidity in the rat: methylnaloxonium mapping study

Weinger, Matthew B.; Smith, N. Ty; Blasco, T. A.; Koob, George F.

doi:10.1016/0006-8993(91)90052-w

Cited by 28 publications

(9 citation statements)

References 39 publications

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“…The decrease in tidal volume produced by fentanyl may result from an increase in respiratory muscle stiffness and/or changes in phrenic motor activity during inspiration expiration (Campbell, Weinger, & Quinn, 1995). Both fentanyl and alfentanil have been reported to cause profound muscle stiffness in rodents by an action on μ-opioid receptors in the CNS (Lui, Chang, Lee, & Chan, 1993;Weinger, Smith, Blasco, & Koob, 1991). Conversely, the hyper locomotor activity induced by heroin in mice may stimulate respiration and obscure any decrease in tidal volume.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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%

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

show abstract

“…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

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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 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

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“…As a result of these symptoms, patients were unable to undergo spontaneous respiration, and ventilatory support was required. In animals, rigidity in the gastrocnemius soleus muscles of the hind limb (Blasco et al., 1986 ; Havemann & Kuschinsky, 1981 ; Havemann et al., 1982 , 1980 ; Lui et al., 1990 ; Ossowska et al., 1986 ; Themann et al., 1984 , 1986 ; Tsou et al., 1989 ; Turski et al., 1982a , 1982b , 1982c ; Vankova et al., 1996 ; Wand et al., 1973 ; Wardas et al., 1987 ; Weinger et al., 1988 , 1989 , 1991 , 1995 ), rectus abdominus muscles (Lui et al., 1989 ; Tsou et al., 1989 ), and sacrococcygeus dorsi lateralis muscles (Fu et al., 1994 , 1997 ; Lai & Lui, 2000 ; Lee et al., 1995a , 1995b ; Lui et al., 1993 ; Wang et al., 1994 ) were observed in rats, and chest wall compliance was decreased in rabbits (Soares et al., 2014 ). In guinea pigs, increased abdominal tone and rigidity have been observed (Brent & Bot, 1992 ).…”

Section: Discussionmentioning

confidence: 99%

Fentanyl‐induced muscle rigidity in a dog during weaning from mechanical ventilation after emergency abdominal surgery: A case report

Sasaki

Rabozzi²,

Kasai

et al. 2022

Veterinary Medicine & Sci

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A 22.5‐kg, 8.4‐year‐old female mixed breed dog was presented for an emergency ovariohysterectomy for pyometra. No neurological abnormalities were observed on preoperative physical examination. Surgery was completed uneventfully under fentanyl‐ and sevoflurane‐based anaesthesia. Cardiorespiratory indices remained stable under mechanical ventilation throughout the procedure. Approximately 23 min after the discontinuation of fentanyl infusion, the investigator noticed jaw closure and stiffness and thoraco‐abdominal muscle rigidity. To rule out fentanyl‐induced muscle rigidity, naloxone was administered. Following administration of naloxone, there was a return of spontaneous respiratory effort, indicated by capnogram and visible chest wall excursion. Based on the clinical signs and response to naloxone administration, the dog was diagnosed with suspected fentanyl‐induced muscle rigidity. Six minutes after the return of spontaneous respiration, the dog was extubated uneventfully without additional naloxone administration. During 4 days of postoperative hospitalization, no recurrent muscle rigidity was observed, and the patient was discharged safely. The total dose of fentanyl administered was 0.61 mg (27 μg kg −1 ).

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Brain sites mediating opiate-induced muscle rigidity in the rat: methylnaloxonium mapping study

Cited by 28 publications

References 39 publications

Fentanyl depression of respiration: Comparison with heroin and morphine

Fentanyl depression of respiration: Comparison with heroin and morphine

Fentanyl depression of respiration: comparison with heroin and morphine

Fentanyl‐induced muscle rigidity in a dog during weaning from mechanical ventilation after emergency abdominal surgery: A case report

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