Delta-1 opioid agonist acutely increases hypoxic tolerance.
Severe, intermittent hypoxia (hypoxic conditioning) induces an acute adaptation such that survival time during a subsequent hypoxic challenge is increased. The opioid antagonist, naloxone, and the delta-selective antagonists, naltrindole and 7-benzylide-nenaltrexone (BNTX), block this adaptation. The current study continued the pharmacological characterization of this acute adaptation to hypoxia by using selective opioid agonists. [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (1 mg/kg s.c.), U50488H [trans-(+/-)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl] benzeacetamide methane sulfonate]; 30 mg/kg s.c.] and [D-Pen2,D-Pen5]-enkephalin (DPDPE; 100 mg/kg s.c.) further augmented the hypoxic conditioning induced increase in survival time. DPDPE (56.1 mg/kg of peptide i.v.) increased survival time of naive mice independently of hypoxic conditioning and decreased body temperature. The DPDPE-induced increase in survival time was blocked by the delta-1-selective antagonist, BNTX (0.6 mg/kg s.c.), but not by the delta-2-selective antagonist, naltrindole (10 mg/kg s.c.). However, the DPDPE-induced decrease in body temperature was not blocked by either BNTX or naltrindole. These results supported our hypothesis that the mechanism of acute hypoxic adaptation involves an endogenous delta-1 opioid pathway and demonstrated that activation of a delta-1 receptor mimicked acute hypoxic adaptation induced by intermittent hypoxia.
Mayfield
K P
KP
University of Michigan Medical School, Department of Physiology, Ann Arbor.
D'Alecy
L G
LG
D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D000222:Adaptation, Physiological; D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D020881:Enkephalin, D-Penicillamine (2,5)-; D004745:Enkephalins / Q000494:pharmacology; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000502:physiology*
D001597:Benzylidene Compounds; D004745:Enkephalins; D011759:Pyrrolidines; D017465:Receptors, Opioid, delta; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C077358:7-benzylidenenaltrexone; D009271:Naltrexone; D019900:3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; D020881:Enkephalin, D-Penicillamine (2,5)-