Selective cardiorespiratory effects mediated by mu opioid receptors in the nucleus ambiguus

doi:10.1016/0028-3908(84)90248-X

Neuropharmacology

Volume 23, Issue 4, April 1984, Pages 407-415

https://doi.org/10.1016/0028-3908(84)90248-X Get rights and content

Abstract

The respiratory and cardiovascular effects of the highly selective mu opioid agonist, d-Ala², MePhe⁴, Gly-ol⁵ enkephalin (DAGO) and the relatively selective delta agonist, D-Ala², d-Leu⁵ enkephalin (DADL) were compared following injection (0.1 μl) into the nucleus ambiguus (NA) of spontaneously-breathing and artificially-respired, pentobarbital-anesthetized rats. In non-ventilated animals, the opioids elicited dose-related (3 × 10⁻¹¹ −3 × 10⁻⁹ M), naloxone-reversible depression of respiratory rate (RR) without altering the tidal volume. Mean arterial pressure (MAP) was unchanged at small doses and decreased at the largest dose; heart rate (HR) was unchanged. In artificially-respired animals, both peptides elicited dose-related, naloxone-reversible increases in mean arterial pressure and heart rate; DAGO was significantly more potent than DADL (P < 0.01). Given the relative potency and selectivity of the opioids tested, these findings are consistent with the conclusion that mu receptors may selectively mediate the respiratory and cardiovascular actions of opioids in an important brain stem cardiorespiratory center in the rat. Moreover, these data indicate the importance of respiratory effects on the cardiovascular activity of centrally administered opioids.

References (51)

S.F. Atweh et al.
Autoradiographic localization of opiate receptors in rat brain I. Spinal cord and lower medulla
Brain Res.
(1977)
P. Bolme et al.
Cardiovascular effects of morphine and opioid peptides following intracisternal administration in chloralose-anesthetized rats
Eur. J. Pharmac.
(1978)
H.L. Borison
Central nervous system respiratory depressant-narcotic analgesics
Pharmac. Ther.
(1977)
H.L. Borison
Central nervous system respiratory depressant-anesthetics, hypnotics, sedatives and other respiratory depressants
Pharmac. Ther.
(1978)
K-J. Chang et al.
Multiple opiate receptors
J. biol. Chem.
(1979)
M. Denavit-Saubie et al.
Effects of opiates and methionine-enkephalin on pontine and bulbar respiratory neurones of the cat
Brain Res.
(1978)
G. Feuerstein et al.
Differential cardiovascular effects of μ, σ and κ opiate agonists at discrete hypothalamic sites in the anesthetized rat
Life Sci.
(1982)
J. Florez et al.
Respiratory effects of B-endorphin, d-Ala²-Met-enkephalinamide and met-enkephalin injected into the lateral ventricle and the pontomedullary subarachnoid space
Brain Res.
(1980)
B.K. Handa et al.
Analogs of β-LPH 61–64 possessing selective agonist activity at μ-opiate receptors
Eur. J. Pharmac.
(1981)
A.H. Hassen et al.
μ receptors and opioid cardiovascular effects in the NTS of rats
Peptides
(1982)

A.H. Hassen et al.

δ vs. μ receptors: Cardiovascular effects of opiate agonists microinjected into Nucleus Tractus Solitarius of cats

Regul. Peptides

(1982)

A.H. Hassen et al.

Differential cardiovascular effects mediated by mu and kappa opiate receptors in hindbrain nuclei

Peptides

(1983)

A.H. Hassen et al.

Selective respiratory depressant action of morphine compared to meperidine in the cat

Eur. J. Pharmac.

(1976)

M. Laubie et al.

Indication for central vagal endorphinergic control of heart rate in dogs

Eur. J. Pharmac.

(1981)

M. Laubie et al.

Vagal bradycardia produced by microinjection of morphine-like drugs into the Nucleus Ambiguus in anesthetized dogs

Eur. J. Pharmac.

(1979)

H. Matsuguchi et al.

Blood pressure and heart rate responses to microinjection of vasopressin into the nucleus tractus solitarius region of the rat

Neuropharmacology

(1982)

M.A. Petty et al.

Cardiovascular effects of β-endorphin after microinjection into the Nucleus Tractus Solitarii of the anesthetized rat

Eur. J. Pharmac.

(1982)

A. Pfeiffer et al.

Opiate receptor binding sites in human brain

Brain Res.

(1982)

T.C. Ritchie et al.

The relationship of the medullary catecholamine containing neurons to the vagal motor nuclei

Neuroscience

(1982)

G. Rondouin et al.

Effects of sulfonated leu-enkephalin applied iontophoretically to cat respiratory neurons

Neuropharmacology

(1981)

G.E. Sander et al.

Cardiopulmonary pharmacology of enkaphalins in the conscious dog

Peptides

(1981)

K. Yoshimura et al.

Potency of three opiate antagonists to reverse the inhibitory activity of dynorphin, enkephalins and opioid-like alkaloids on the guinea pig ileum

Eur. J. Pharmac.

(1982)

P. Zandberg et al.

Localization of catecholaminergic receptor sites in the Nucleus Tractus Solitarius involved in the regulation of arterial blood pressure

Prog. Brain Res.

(1977)

M. Bellet et al.

Central cardiovascular effects of narcotic analgesics and enkephalins in rats

Br. J. Pharmac.

(1980)

G.W. Bradley et al.

Steady state effects of CO₂ and temperature on the relationship between lung volume and inspiratory duration (Hering-Breuer threshold curve)

Acta physiol. scand.

(1974)

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Similar to our finding, the delta-opioid receptor antagonist did not inhibit chronic morphine-induced respiratory depression in rats (Ananthan, 2006; Kozaki et al., 2000). The nucleus tractus solitarius (inspiratory center) and nucleus ambiguous (expiratory center) in the brain stem are related to opioid-induced respiratory depression (Hassen et al., 1982, 1984). It has been shown that about 50% of neurons in the nucleus tractus solitarius were hyperpolarized by activation of mu-opioid receptors, but there was no postsynaptic effect of delta or kappa opioid receptor in the nucleus tractus solitarius neurons (Rhim et al., 1993).
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Opioids are known to induce respiratory depression. We aimed to characterize in rats the effects of four opioids on arterial blood gases and plethysmography after intraperitoneal administration at 80% of their LD₅₀ in order to identify opioid molecule-specific patterns and classify response severity. Opioid-receptor (OR) antagonists, including intravenous 10 mg kg⁻¹-naloxonazine at 5 min [mu-OR antagonist], subcutaneous 30 mg kg⁻¹-naloxonazine at 24 h [mu1-OR antagonist], subcutaneous 3 mg kg⁻¹-naltrindole at 45 min [delta-OR antagonist], and subcutaneous 5 mg kg⁻¹-Nor-binaltorphimine at 6 h [kappa-OR antagonist] were pre-administered to test the role of each OR. Methadone, morphine, and fentanyl significantly decreased PaO₂ (P < 0.001) and increased PaCO₂ (P < 0.05), while buprenorphine only decreased PaO₂ (P < 0.05). While all opioids significantly increased inspiratory time (T_I, P < 0.001), methadone and fentanyl also increased expiratory time (T_E, P < 0.05). Intravenous 10 mg kg⁻¹-naloxonazine at 5 min completely reversed opioid-related effects on PaO₂ (P < 0.05), PaCO₂ (P < 0.001), T_I (P < 0.05), and T_E (P < 0.01) except in buprenorphine. Subcutaneous 30 mg kg⁻¹-naloxonazine at 24 h completely reversed effects on PaCO₂ (P < 0.01) and T_E (P < 0.001), partially reversed effects on T_I (P < 0.001), and did not reverse effects on PaO₂. Naltrindole reversed methadone-induced T_E increases (P < 0.01) but worsened fentanyl's effect on PaCO₂ (P < 0.05) and T_I (P < 0.05). Nor-binaltorphimine reversed morphine- and buprenorphine-induced T_I increases (P < 0.001) but worsened methadone's effect on PaO₂ (P < 0.05) and morphine (P < 0.001) and buprenorphine's (P < 0.01) effects on pH. In conclusion, opioid-related respiratory patterns are not uniform. Opioid-induced hypoxemia as well as increases in T_I and T_E are caused by mu-OR, while delta and kappa-OR roles appear limited, depending on the specific opioid. Regarding severity of opioid-induced respiratory effects at 80% of their LD₅₀, all drugs increased T_I. Methadone and fentanyl induced hypoxemia, hypercapnia, and T_E increases, morphine caused both hypoxemia and hypercapnia while buprenorphine caused only hypoxemia.
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Anatomical and in vitro studies suggest that mu opioid receptors (MOR) on pre-Bötzinger complex neurons are responsible for opioid induced respiratory depression (Grey et al., Science 286 (1999) 1566). However, mu opioid agonists injected in vivo, in other regions of the ventral respiratory group (VRG), produce respiratory depression, suggesting that opioids are widely distributed in the VRG. We therefore re-examined the distribution of the MOR in the ventral medulla and found MOR-immunoreactive neurons and terminals in all subdivisions of the VRG. Furthermore, we determined, in rats, the effects of a MOR agonist (endomorphin-1, 10 mM, 60 nl, unilateral), microinjected into different subdivisions of the VRG, on phrenic nerve activity. Endomorphin-1 produced changes in phrenic nerve frequency and amplitude, throughout the VRG. Unexpectedly, endomorphin-1 microinjected into the Bötzinger and pre-Bötzinger complexes consistently increased phrenic nerve frequency. These results support the widespread distribution of MOR in the VRG and also indicate that endomorphin-1, a postulated endogenous ligand, may differentially regulate respiration.
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Selective cardiorespiratory effects mediated by mu opioid receptors in the nucleus ambiguus

Abstract

Brain Res.

Eur. J. Pharmac.

Pharmac. Ther.

Pharmac. Ther.

J. biol. Chem.

Brain Res.

Life Sci.

Brain Res.

Eur. J. Pharmac.

Peptides

Regul. Peptides

Peptides

Eur. J. Pharmac.

Eur. J. Pharmac.

Eur. J. Pharmac.

Neuropharmacology

Eur. J. Pharmac.

Brain Res.

Neuroscience

Neuropharmacology

Peptides

Eur. J. Pharmac.

Prog. Brain Res.

Central cardiovascular effects of narcotic analgesics and enkephalins in rats

Br. J. Pharmac.

Steady state effects of CO2 and temperature on the relationship between lung volume and inspiratory duration (Hering-Breuer threshold curve)

Acta physiol. scand.

Steady state effects of CO₂ and temperature on the relationship between lung volume and inspiratory duration (Hering-Breuer threshold curve)