Respiratory function in adult mice lacking the mu-opioid receptor: role of delta-receptors.
Mice lacking the mu-opioid receptor (MOR) provide a unique model to determine whether opioid receptors are functionally interactive. Recent results have shown that respiratory depression produced by delta-opioid receptor agonists is suppressed in mice lacking the mu-opioid receptor. Here we investigated the involvement of mu- and delta-opioid receptors in the control of ventilation and mu/delta receptor interactions in brainstem rhythm-generating structures. Unrestrained MOR-/- and wild-type mice showed similar ventilatory patterns at rest and similar chemosensory responses to hyperoxia (100% O2), hypoxia (10% O2) or hypercapnia (5%CO2-95%O2). Blockade of delta-opioid receptors with naltrindole affected neither the ventilatory patterns nor the ventilatory responses to hypoxia in MOR-/- and wild-type mice. In-vitro, respiratory neurons were recorded in the pre-Bötzinger complex of thick brainstem slices of MOR-/- and wild-type young adult mice. Respiratory frequency was not significantly different between these two groups. The delta2 receptor agonist deltorphin II (0.1-1.0 microM) decreased respiratory frequency in both groups whereas doses of the delta1 receptor agonist enkephalin[D-Pen2,5] (0.1-1.0 microM) which were ineffective in wild-type mice significantly decreased respiratory frequency in MOR-/- mice. We conclude that deletion of the mu-opioid receptor gene has no significant effect on ensuing respiratory rhythm generation, ventilatory pattern, or chemosensory control. In MOR-/- mice, the loss of respiratory-depressant effects of delta2-opioid receptor agonists previously observed in vivo does not result from a blunted response of delta receptors in brainstem rhythm-generating structures. These structures show an unaltered response to delta2-receptor agonists and an augmented response to delta1-receptor agonists.
Morin-Surun
M P
MP
Neurobiologie Génétique et Intégrative, Institut de Neurobiologie Alfred Fessard, CNRS, F-91198 Gif-sur-Yvette Cedex, France.
Boudinot
E
E
Dubois
C
C
Matthes
H W
HW
Kieffer
B L
BL
Denavit-Saubié
M
M
Champagnat
J
J
Foutz
A S
AS
D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D005260:Female; D008297:Male; D008526:Medulla Oblongata / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout / Q000002:abnormalities / Q000378:metabolism*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D009924:Organ Culture Techniques; D017465:Receptors, Opioid, delta / Q000187:drug effects / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000172:deficiency* / Q000235:genetics; D012125:Respiratory Center / Q000187:drug effects / Q000378:metabolism*; D012143:Respiratory Physiological Phenomena / Q000187:drug effects*
D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C060209:deltorphin II, Ala(2)-; D009271:Naltrexone; D020881:Enkephalin, D-Penicillamine (2,5)-; C055382:naltrindole