7-benzylidenenaltrexone and Disease-Models--Animal

Opioids are well known for their robust analgesic effects. Chronic activation of mu opioid receptors (MOPs) is, however, accompanied by various unwanted effects such as analgesic tolerance. Among other mechanisms, interactions between MOPs and delta opioid receptors (DOPs) are thought to play an important role in morphine-induced behavioral adaptations. Interestingly, certain conditions such as inflammation enhance the function of the DOP through a MOP-dependent mechanism. Here, we investigated the role of DOPs during the development of morphine tolerance in an animal model of chronic inflammatory pain. Using behavioral approaches, we first established that repeated systemic morphine treatment induced morphine analgesic tolerance in rats coping with chronic inflammatory pain. We then observed that blockade of DOPs with subcutaneous naltrindole (NTI), a selective DOP antagonist, significantly attenuated the development of morphine tolerance in a dose-dependent manner. We confirmed that this effect was DOP mediated by showing that an acute injection of NTI had no effect on morphine-induced analgesia in naive animals. Previous pharmacological characterizations revealed the existence of DOP subtype 1 and DOP subtype 2. As opposed to NTI, 7-benzylidenenaltrexone and naltriben were reported to be selective DOP subtype 1 and DOP subtype 2 antagonists, respectively. Interestingly, naltriben but not 7-benzylidenenaltrexone was able to attenuate the development of morphine analgesic tolerance in inflamed rats. Altogether, our results suggest that targeting of DOP subtype 2 with antagonists provides a valuable strategy to attenuate the analgesic tolerance that develops after repeated morphine administration in the setting of chronic inflammatory pain.

Topics: Analgesics, Opioid; Animals; Benzylidene Compounds; Chronic Pain; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Freund's Adjuvant; Hindlimb; Inflammation; Male; Morphine; Naltrexone; Narcotic Antagonists; Rats, Sprague-Dawley; Receptors, Opioid, delta

Functional interactions between mu- and delta-opioid receptors (MOPr and DOPr, respectively) are implicated in morphine tolerance and dependence. The contribution of DOPr to the conditioned rewarding effects of morphine and the enhanced conditioned response that occurs after repeated morphine administration is unknown. This issue was addressed with the conditioned place preference procedure (CPP).. Rats received home cage injections of saline or morphine (5.0 mg/kg/day x 5 days) before conditioning. For sensitization studies, DOPr antagonists (DOPr1/2: naltrindole, DOPr2: naltriben, DOPr1: 7-benzylidenenaltrexone) were administered before morphine injections. Conditioning sessions (2 morphine; 2 saline) commenced 3 days later. To assess the influence of acute DOPr blockade on the conditioning of morphine reward in naïve animals, 3 morphine and 3 saline conditioning sessions were employed. Antagonists were administered before morphine conditioning sessions.. Morphine was ineffective as a conditioning stimulus after two conditioning sessions in naïve rats. However, doses > or = 3.0 mg/kg produced significant CPP in morphine pre-exposed rats, confirming that sensitization develops to the conditioned rewarding effects of morphine. In animals that received morphine pre-exposure with naltrindole or naltriben but not 7-benzylidenenaltrexone, sensitization was prevented. No attenuation of morphine CPP was observed in animals that received DOPr antagonists acutely, before conditioning sessions.. These data indicate a critical role of DOPr systems in mediating sensitization to the conditioned rewarding effects of morphine. The efficacy of naltrindole and naltriben in preventing the enhanced response to morphine suggest the specific involvement of DOPr2 in the sensitization process.

Topics: Analysis of Variance; Animals; Association Learning; Behavior, Animal; Benzylidene Compounds; Conditioning, Classical; Disease Models, Animal; Male; Morphine Dependence; Naltrexone; Narcotic Antagonists; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk; Receptors, Opioid, delta; Receptors, Opioid, mu; Reinforcement, Psychology; Statistics, Nonparametric

Mammalian hibernation biology is now known to be mediated by delta opioids. The altered myocellular physiology of hibernation closely parallels that of hypothermic ischemia used to protect the heart for cardiac surgery.. The present study examined the interaction of delta opioid agonists and antagonists on myocardial tolerance to ischemia. By means of a nonhibernating isolated rabbit heart model, functional and metabolic myocardial parameters were assessed during nonischemic baseline and postischemic recovery periods. Control hearts with standard cardioplegic protection alone were compared with those with cardioplegia plus preperfusion with a delta opioid agonist, a delta opioid antagonist, or both. All hearts were then subjected to 2 hours of global ischemia. Compared with cardioplegia alone, postischemic left ventricular developed pressure, coronary flows, and myocardial oxygen consumption were all increased with administration of delta opioid agonists and decreased below baseline with delta opioid antagonists. Functional recovery of left ventricular developed pressure was improved with opioids (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist: 65 +/- 5 mm Hg, P <.01) and inhibited with antagonists (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid antagonist: 17 +/- 5 mm Hg, P <.05), and true to form, the protective opioid effect was negated when combined with an antagonist (control hearts: 36 +/- 3 mm Hg vs hearts with cardioplegia plus delta opioid agonist and delta opioid antagonist: 42 +/- 4 mm Hg, P = not significant).. This study demonstrates that cardiac tolerance to ischemia may be mediated by delta opioids.

Topics: Analgesics, Opioid; Animals; Benzylidene Compounds; Cardiac Surgical Procedures; Coronary Circulation; Disease Models, Animal; Drug Evaluation, Preclinical; Enkephalin, D-Penicillamine (2,5)-; Heart Arrest, Induced; Hypothermia, Induced; Ischemic Preconditioning, Myocardial; Myocardial Ischemia; Naltrexone; Narcotic Antagonists; Organ Size; Oxygen Consumption; Rabbits; Receptors, Opioid, delta; Recovery of Function; Stroke Volume; Ventricular Pressure