Activity of the delta-opioid receptor is partially reduced, whereas activity of the kappa-receptor is maintained in mice lacking the mu-receptor.
Previous pharmacological studies have indicated the possible existence of functional interactions between mu-, delta- and kappa-opioid receptors in the CNS. We have investigated this issue using a genetic approach. Here we describe in vitro and in vivo functional activity of delta- and kappa-opioid receptors in mice lacking the mu-opioid receptor (MOR). Measurements of agonist-induced [35S]GTPgammaS binding and adenylyl cyclase inhibition showed that functional coupling of delta- and kappa-receptors to G-proteins is preserved in the brain of mutant mice. In the mouse vas deferens bioassay, deltorphin II and cyclic[D-penicillamine2, D-penicillamine5] enkephalin exhibited similar potency to inhibit smooth muscle contraction in both wild-type and MOR -/- mice. delta-Analgesia induced by deltorphin II was slightly diminished in mutant mice, when the tail flick test was used. Deltorphin II strongly reduced the respiratory frequency in wild-type mice but not in MOR -/- mice. Analgesic and respiratory responses produced by the selective kappa-agonist U-50,488H were unchanged in MOR-deficient mice. In conclusion, the preservation of delta- and kappa-receptor signaling properties in mice lacking mu-receptors provides no evidence for opioid receptor cross-talk at the cellular level. Intact antinociceptive and respiratory responses to the kappa-agonist further suggest that the kappa-receptor mainly acts independently from the mu-receptor in vivo. Reduced delta-analgesia and the absence of delta-respiratory depression in MOR-deficient mice together indicate that functional interactions may take place between mu-receptors and central delta-receptors in specific neuronal pathways.
Matthes
H W
HW
Unité Propre de Recherche 9050 Centre National de la Recherche Scientifique, Ecole Supérieure de Biotechnologie de Strasbourg Université Louis Pasteur, F-67400 Illkirch, Strasbourg, France.
Smadja
C
C
Valverde
O
O
Vonesch
J L
JL
Foutz
A S
AS
Boudinot
E
E
Denavit-Saubié
M
M
Severini
C
C
Negri
L
L
Roques
B P
BP
Maldonado
R
R
Kieffer
B L
BL
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer / Q000494:pharmacology; D000700:Analgesics / Q000494:pharmacology; D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D001572:Benzofurans / Q000494:pharmacology; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism*; D009842:Oligopeptides / Q000494:pharmacology; D010147:Pain Measurement; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000235:genetics* / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012119:Respiration / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
D000700:Analgesics; D018712:Analgesics, Non-Narcotic; D000701:Analgesics, Opioid; D000889:Anti-Arrhythmia Agents; D001572:Benzofurans; D004745:Enkephalins; D009842:Oligopeptides; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C060209:deltorphin II, Ala(2)-; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020881:Enkephalin, D-Penicillamine (2,5)-; D019204:GTP-Binding Proteins; C067110:enadoline