7-benzylidenenaltrexone and Hypoxia

We studied the role of opioid receptor subtypes in improvement of the functional state of the heart during reperfusion after adaptation to continuous normobaric hypoxia. To this end, male Wistar rats were subjected to continuous normobaric hypoxia (12% O

Topics: Adaptation, Physiological; Animals; Benzylidene Compounds; Creatine Kinase; Hypoxia; Male; Myocardial Reperfusion Injury; Myocardium; Naloxone; Naltrexone; Narcotic Antagonists; Oligopeptides; Organ Culture Techniques; Peptides; Rats; Rats, Wistar; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Tetrahydroisoquinolines

Previously, it has been observed that mu-opioid receptors contribute to while kappa-opioid receptors oppose pial artery dilation in response to hypoxia. The present study was designed to investigate the contribution of delta 1- and delta 2-opioid receptor activation to hypoxia-induced pial vasodilation. Newborn pigs equipped with a closed cranial window were used to measure pial artery diameter and collect cortical periarachnoid CSF for assay of opioids. Hypoxia increased CSF leucine enkephalin (a delta -agonist) from 36 +/- 6 to 113 +/- 17 pg/ml (n = 5). Hypoxia-induced pial artery vasodilation was attenuated during moderate hypoxia (PaO2 approximately 35 mm Hg), while this response was blunted during severe hypoxia (PaO2 approximately 25 mm Hg), by the delta 1-opioid receptor antagonist 7-benzylidenenaltrexone (BNTX; 10(-8) M) (23 +/- 2 vs. 13 +/- 2 and 34 +/- 6 vs. 10 +/- 3% for moderate and severe hypoxia in the absence and presence of BNTX, respectively; n = 5). In contrast, the delta 2-opioid receptor antagonist naltrindole (10(-9) M) blunted pial vasodilation during moderate hypoxia, but only attenuated the vasodilator response during severe hypoxia (22 +/- 2 vs. 8 +/- 2 and 33 +/- 4 vs. 23 +/- 4% for moderate and severe hypoxia in the absence and presence of naltrindole, respectively; n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Animals, Newborn; Benzylidene Compounds; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Female; Hypoxia; Male; Naltrexone; Narcotic Antagonists; Oligopeptides; Pia Mater; Receptors, Opioid, delta; Receptors, Opioid, mu; Swine; Vasodilation

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.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Adaptation, Physiological; Animals; Benzylidene Compounds; Body Temperature; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Hypoxia; Male; Mice; Naltrexone; Pyrrolidines; Receptors, Opioid, delta

Previously an acute adaptation to hypoxia was induced by intermittent, severe hypoxia and this conditioned increase in survival time during subsequent hypoxia was blocked by naloxone. The current study further defined the opioid nature and the receptor type(s) involved in hypoxic adaptation by the use of (+)-naloxone (inactive isomer) and selective opioid antagonists. (+)-Naloxone failed to change significantly the survival times of hypoxic or sham conditioned mice during subsequent hypoxia. The selective opioid antagonists, 7-benzylidenenaltrexone, naltrindole, beta-funaltrexamine and norbinaltorphimine were administered subcutaneously before hypoxic or sham conditioning. The delta-1 and delta-2 selective antagonists, 7-benzylidenenaltrexone and naltrindole respectively, blocked the hypoxic conditioning-induced increase in survival time. The lowest effective 7-benzylidenenaltrexone dose was 3000-fold lower than the lowest effective naltrindole dose indicating that the acute adaptation to hypoxia was predominantly sensitive to delta-1 blockade. Neither the mu antagonist, beta-funaltrexamine, nor the kappa antagonist, norbinaltorphimine, significantly changed survival time in sham or hypoxic conditioned mice. These results support a delta-1 receptor mediated mechanism of acute adaptation to hypoxia.

Topics: Adaptation, Physiological; Animals; Benzylidene Compounds; Hypoxia; Male; Mice; Naltrexone; Narcotic Antagonists; Receptors, Opioid, delta