Effects Of Mu Opioid Agonists Research Articles

Quantitative proteomic analysis reveals the effects of mu opioid agonists on HT22 cells.

Introduction: At present, the mu opioid receptor is the most important neuroaesthetics receptor in anesthesiology research, and the damage that it does to the nervous system is unknown. Methods: We investigated the effects of loperamide, an agonist of the mu opioid receptor, on protein expression in HT22 cells using stable isotope labeling of amino acids in cell culture (SILAC), immobilized metal affinity chromatography (IMAC) enrichment, and high-resolution liquid chromatography-tandem mass spectrometry (LC-MS/MS). A total of 7,823 proteins were identified. Results and Discussion: Bioinformatic analysis revealed that mu opioid receptor agonism can induce distinct changes in the proteome of HT22 cells. These findings improve our understanding of narcotic drugs.

Interactive effects of (±)-trans-U50488 and its stereoisomers with cannabinoids

The adverse effects of mu opioid agonists have spurred a renewed interest in using kappa opioid receptor (KOR) agonists as analgesics. KOR agonists also have potential for development as diuretics for the treatment of edema and hypertension. Here, we evaluated the discriminative stimulus, antinociceptive, and diuretic effects of the kappa agonist (±)-trans-U-50488 and its stereoisomers (−)-(1S,2S)-U-50488 or (+)-(1R,2R)-U-50488) alone and in combination with the cannabinoid agonist (−)-CP 55,940. To establish (±)-U-50488 as a discriminative stimulus, rats (n = 12) were trained to discriminate intraperitoneal (i.p.) administration of 5.6 mg/kg of (±)-trans-U-50488 from saline under a fixed-ratio 20 (FR-20) schedule of food reinforcement. Then, antinociception was assessed using two procedures: warm water tail withdrawal and von Frey paw withdrawal. Diuretic effects were assessed in separate rats (n = 6/group). Doses of (±)-U-50488 and (−)-U-50488 that served as discriminative stimuli produced significant increases in urine output, but at lower doses than those that produced antinociception. In contrast, (+)-U-50488 alone had no discriminative stimulus or diuretic effects at the doses tested, but did produce antinociception in the von Frey assay. When three cannabinoids and morphine were tested in the (±)-U-50488 discrimination procedure to determine the similarity of these drugs' discriminative stimulus effects to those for (±)-U-50488, the rank order similarity was (−)-CP 55,940 > (−)-trans-THC > (+)-WIN 55,212–2 ≥ morphine. (−)-CP 55,940 alone (0.056 mg/kg) partially substituted for the discriminative stimulus effects of (±)-U-50488 and produced significant diuretic and antinociceptive effects. (−)-CP 55,940 in combination with (±)-U-50488 also produced a two-fold leftward shift in the discriminative stimulus curve for (±)-U-50488, and near-additive antinociception with (±)-U-50488 and (+)-U-50488. Further, the diuretic effect of (−)-CP 55,940 was enhanced by a dose of (+)-U50488, which itself did not alter urine output. These data together indicate that a combination of cannabinoid and kappa opioid agonists can enhance diuresis, but may have limited potential for serving as opioid-sparing pharmacotherapeutics for treatment of pain.

Nalfurafine modulates the reinforcing effects of oxycodone in male and female adolescent C57BL/6J mice

Addiction to prescription opioid, such as oxycodone, has affected millions of adolescents and young adults. Kappa opioid receptor (KOP-r) agonist can counterbalance the euphoria effects of mu opioid agonists like oxycodone. Nalfurafine is a KOP-r agonist. The current study examined how nalfurafine affected the reinforcing-effect of oxycodone in adolescent male and female mice using intravenous self-administration (SA) and conditioned place preference (CPP) paradigms.Adolescent mice (5 week-old) first received surgery for catheter implantation. After recovery, mice were then placed into the SA chambers and allowed to self-administer oxycodone, 2 h per day for 14 days. Following 14-day oxycodone SA, mice were injected with saline and a single dose of nalfurafine (10, 20, 30, 40 μg/kg, s.c.) 10 min before each oxycodone SA session for 5 consecutive days. The mice were then injected with Nor-BNI (10 mg/kg, i.p.) 24 h before oxycodone SA following injection of nalfurafine (40 μg/kg, s.c.). Separate groups of male and female adolescent mice underwent oxycodone CPP or hot plate test with or without nalfurafine pre-injection. Nalfurafine decreased oxycodone SA in a dose dependent manner. Nor-BNI blocked the effect of nalfurafine on oxycodone SA. Nalfurafine significantly attenuated the oxycodone-induced hyperlocomotor activities and CPP, but enhanced oxycodone-induced analgesia. In conclusion, nalfurafine reduced the reinforcing effects of oxycodone in male and female adolescent mice. Nalfurafine also increased oxycodone-induced antinociception.

The Effect of Benfotiamine on Mu-opioid Receptor Mediated Antinociception in Experimental Diabetes

Diabetic neuropathy is a prevalent, disabling disorder. Currently, the only treatments available to patients with diabetic neuropathy are glucose control and pain management. B vitamin present neuroprotective effects, which are suggested to be related to their analgesic action in various models of neuropathic pain. According to our literature knowledge there is no report about antinociceptive effects of thiamine as benfotiamine and opioids together in diabetic mice. The purpose of this study was to determine the effects of benfotiamine on the antinociception produced by mu-opioid receptor agonist fentanyl in diabetic mice. The effects of benfotiamine on antinociception produced by fentanyl in diabetic mice were studied in 4 groups. Antinociceptive effect was determined with tail flick, hot plate and formalin test. Our results showed that, mu-opioid agonist fentanyl in benfotiamine applied diabetic group caused more potent antinociceptive effect than in diabetic group without benfotiamine treatment. In brief benfotiamine supplement in diet did not bring out antinociceptive effect itself, but during development of STZ diabetes, benfotiamine replacement increased the antinociceptive effect of fentanyl in mice tail-flick test. This effect is probably due to the replacement of benfotiamine efficiency occurring in diabetes mellitus. Finally, we suppose that oral benfotiamine replacement therapy may be useful to ameliorate analgesic effect of mu-opioid agonists on neuropathic pain in diabetic case.

Interaction between Mu and Delta Opioid Receptor Agonists in an Assay of Capsaicin-Induced Thermal Allodynia in Rhesus Monkeys

Delta opioid agonists enhance antinociceptive effects of mu-opioid agonists in many preclinical assays of acute nociception, but delta/mu interactions in preclinical models of inflammation-associated pain have not been examined. This study examined interactions between the delta agonist SNC80 [(+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide] and the mu agonist analgesics methadone, morphine, and nalbuphine in an assay of capsaicin-induced thermal allodynia in rhesus monkeys. Thermal allodynia was produced by topical application of capsaicin to the tail. Antiallodynic effects of methadone, morphine, and nalbuphine were evaluated alone or in combination with fixed proportions of SNC80 identical to proportions previously shown to enhance acute thermal antinociceptive effects of these mu agonists in rhesus monkeys (0.9 : 1 SNC80/methadone; 0.29 : 1 SNC80/morphine; 3.6 : 1 SNC80/nalbuphine). Methadone, morphine, and nalbuphine each produced dose-dependent antiallodynia. SNC80 produced partial antiallodynia up to the highest dose tested (5.6 mg/kg). SNC80 produced a modest, enantioselective, and naltrindole-reversible enhancement of methadone-induced antiallodynia. However, SNC80 did not enhance morphine antiallodynia and only weakly enhanced nalbuphine antiallodynia. Overall, SNC80 produced modest or no enhancement of the antiallodynic effects of the three mu agonists evaluated. These results suggest that delta agonist-induced enhancement of mu agonist antiallodynia may be weaker and less reliable than previously demonstrated enhancement of mu agonist acute thermal nociception.

Effects of Anesthetics on Cancer Recurrence

TO THE EDITOR: We read with great interest the recent article by Weckermann et al on the perioperative activation of disseminated tumor cells in bone marrow of patients with prostate cancer. The authors postulate “unknown perioperatively acting triggers that stimulate outgrowth of DTCs” (disseminated tumor cells). Recent clinical and laboratory data suggest that anesthetic technique may play a role in tumor dissemination and recurrence. This issue has been highlighted in the anesthesia literature in a recent article of the Anesthesia Patient Safety Foundation Newsletter, which reviews the clinical and laboratory data for such an effect. In a retrospective study of prostate cancer, there was a significant difference in the rate of tumor recurrence contingent on the type of anesthesia used. A small retrospective study in breast cancer had similar findings. A large, multicenter, prospective, randomized trial investigating the influence of type of anesthesia on breast cancer recurrence is currently underway. In addition to the clinical studies, there is also an evolving basic science literature suggesting that opiates affect tumor growth. Both we and Gupta et al have shown that clinically relevant concentrations of opiates can cause endothelial cell proliferation and migration in vitro. The proangiogenic effect of mu opioid agonists seems to be the result of reciprocal transactivation of the vascular endothelial growth factor receptor. We have also demonstrated that mu opioids induce a defect in barrier function, potentially allowing penetration of tumor cells. The effects of mu agonists on both angiogenesis and barrier function are reversed by tertiary opiate antagonists or by methylnaltrexone, a peripherally acting mu opioid receptor antagonist approved in the United States to treat opioid-induced constipation in patients with advanced illness receiving palliative care when response to laxatives has not been sufficient. If these laboratory studies are confirmed clinically, then the selection of anesthetic technique used during the operative procedure and the possible use of peripheral mu opioid receptor antagonists in the perioperative period may be of potential importance. It would be particularly interesting if the authors were able to review the perioperative records of their patients to see which drugs were administered and what anesthetic techniques were used. We commend the authors for their diligent work and believe that their observations deserve additional investigation.

Role of delta opioid efficacy as a determinant of mu/delta opioid interactions in rhesus monkeys

Delta opioid agonists can selectively enhance the antinociceptive effects of mu opioid agonists without enhancing some other, potentially undesirable mu agonist effects. However, the degree of delta receptor efficacy required to produce this profile of interactions is unknown. To address this issue, the present study examined interactions produced by the mu agonist fentanyl and the intermediate-efficacy delta opioid MSF61 in rhesus monkeys. For comparison, interactions were also examined between fentanyl and the relatively high-efficacy delta agonist SNC243A and the delta antagonist naltrindole, which has negligible efficacy at delta receptors. Two different behavioral procedures were used: (a) a warm-water tail-withdrawal assay of thermal nociception, and (b) an assay of schedule-controlled responding for food reinforcement. Drug interactions within each procedure were evaluated using dose-addition analysis to compare experimental results with expected additivity. Drug interactions across procedures were evaluated using dose–ratio analysis to assess relative potencies to produce antinociception vs. response-rate suppression. As expected, dose-addition analysis found that fentanyl/SNC243A interactions were superadditive in the assay of antinociception but additive in the assay of schedule-controlled responding. Conversely, fentanyl/MSF61 interactions were generally additive in both procedures, and fentanyl/naltrindole interactions were additive or subadditive in both procedures. Dose–ratio analysis found that fentanyl alone produced antinociception and rate suppression with similar potencies. Some fentanyl/SNC243A mixtures produced antinociception with up to 4-fold greater potency than rate-suppression. However, fentanyl/MSF61 and fentanyl/naltrindole mixtures produced antinociception with lower potency than rate suppression. These results suggest that relatively high delta receptor efficacy is required for mu/delta antinociceptive synergy.

Role of delta receptor efficacy as a determinant of delta/mu opioid interactions in rhesus monkeys

Delta opioid agonists have been reported to selectively enhance the antinociceptive effects of mu opioid agonists without enhancing other, potentially untoward mu agonist effects such as sedation, respiratory depression or abuse potential. The purpose of the present study was to examine the role of delta receptor efficacy as a determinant of delta/mu interactions in rhesus monkeys in two different behavioral procedures: (a) an assay of schedule‐controlled responding maintained by food reinforcement, and (b) an assay of thermal nociception. The effects of the selective mu agonist fentanyl were examined in combination with the high‐efficacy delta agonist SNC243A, the intermediate‐efficacy agonist MSF61, or the delta antagonist naltrindole. Fentanyl was tested in combination with three different proportions of each delta opioid. Fentanyl/SNC243A interactions were superadditive in the assay of antinociception and additve in the assay of schedule‐controlled responding. Fentanyl/MSF61 interactions were additive in both procedures, and fentanyl/naltrindole interactions were additive or subadditive in both procedures. These results suggest that high efficacy at delta receptors is required for synergistic delta/mu interactions in assays of antinociception in rhesus monkeys. Supported by R01 DA11460 from NIDA/NIH.

The effect of a systemically active ORL-1 agonist, Ro 64-6198, on the acquisition, expression, extinction, and reinstatement of morphine conditioned place preference

ORL-1 agonists have been proposed as potential therapeutics for substance abuse based on their propensity to counter the effects of mu opioid agonists in several systems, and to inhibit mesolimbic dopamine release, while mostly being devoid of aversive properties. In support of this, ORL-1 agonists have been shown to block the acquisition of morphine conditioned place preference (CPP). We investigated the effect of Ro 64-6198, a systemically active ORL-1 agonist, on the acquisition, expression, extinction, and reinstatement of morphine (20 mg/kg, s.c.) CPP in C57BL6/J mice. Similar to effects obtained with nociceptin/orphanin FQ, Ro 64-6198 (1 mg/kg, i.p.) blocked the acquisition of morphine CPP when given 15 min prior to each drug and vehicle conditioning session. This effect was not due to state dependent learning, since when tested again in the presence of Ro 64-6198 or vehicle no CPP was observed. Administration of Ro 64-6198 (0.3 or 1 mg/kg, i.p.) on the test day alone, in a separate group of animals, failed to block the expression of morphine CPP. Another group of mice was conditioned to morphine to develop CPP, and then exposed to the CPP chambers in the absence of drug once a day for 30 min to extinguish the CPP. Ro 64-6198 (1 mg/kg, i.p.) given 15 min prior to each session during extinction did not affect the rate of extinction. Finally, another group was conditioned to morphine, their CPP extinguished and subsequently reinstated by a priming injection of morphine (20 mg/kg, s.c.). Ro 64-6198 (1 mg/kg, i.p.), given 15 min prior to the priming injection, blocked reinstatement of morphine CPP. These results suggest that Ro 64-6198's effects may be limited to attenuation of the acute rewarding effects of morphine.

Effects of Mu Opioid Agonists Alone and in Combination with Cocaine and D-Amphetamine in Rhesus Monkeys Trained to Discriminate Cocaine

Psychomotor stimulants and mu opioid agonists are often used together by polydrug abusers, and it has been suggested that this form of polydrug abuse may result from the ability of stimulants and mu agonists to enhance each other’s abuse-related effects. To investigate this possibility, the present study examined stimulant-opioid interactions in rhesus monkeys trained to discriminate cocaine. Specifically, the effects of the mu opioid agonists heroin, alfentanil, fentanyl, and morphine administered alone or in combination with cocaine or d-amphetamine were examined in five monkeys trained to discriminate 0.4 mg/kg cocaine (IM) from saline in a two-lever, food-reinforced drug discrimination procedure. When administered alone, the rapid onset mu agonists heroin (0.032–0.32 mg/kg) and alfentanil (0.01–0.1 mg/kg) substituted completely for cocaine in three of five monkeys but produced primarily saline-appropriate responding in the other two monkeys. The slower onset mu agonists fentanyl (0.0056–0.056 mg/kg) and morphine (0.56–10 mg/kg) substituted for cocaine in only one of five monkeys. When administered as pretreatments to cocaine, morphine and fentanyl increased levels of cocaine-appropriate responding produced by low doses of cocaine in some monkeys. Morphine pretreatment also increased levels of cocaine-appropriate responding produced by low doses of amphetamine in some monkeys. However, in other monkeys, morphine and fentanyl pretreatment did not alter the discriminative stimulus effects of cocaine or amphetamine. These results indicate that there are substantial individual difference in the effects of mu agonists in cocaine-discriminating rhesus monkeys. In some monkeys, mu agonists mimic or enhance the discriminative stimulus of cocaine, whereas in other monkeys, mu agonists neither mimic nor enhance the effects of stimulants.

Effects of intracerebroventricular administration of beta-funaltrexamine on DAMGO-stimulated [35S]GTP-gamma-S binding in rat brain sections.

Intracerebroventricular administration of beta-funaltrexamine (beta-FNA) reduces the density of mu opioid receptors as measured by in situ autoradiography by 40-50% throughout the brain, with little regional variation [Martin et al. (1993) J. Pharmacol. Exp. Ther. 267:506-514] Recently an assay has been developed to study opioid stimulation of [35S]GTP-gamma-S binding autoradiographically in situ using slide-mounted brain sections [Sim et al. (1995) Proc. Natl. Acad. Sci. U.S.A. 92:7242-7246]. The present study was undertaken to determine the effect of mu opioid receptor alkylation on G protein activation by the mu opioid agonist DAMGO. Animals were injected intracerebroventricularly with 40 nmol of beta-FNA or saline and sacrificed 24 hours later. DAMGO stimulated [35S]GTP-gamma-S binding with an anatomical specificity consistent with the localization of mu opioid receptors. The percent stimulation by DAMGO ranged from approximately 50 to 100% in the regions studied. beta-FNA significantly decreased G protein activation by DAMGO in regions that are consistent with its reported long-lasting and insurmountable antagonism of the antinociceptive (medial thalamus, central gray) and reinforcing (nucleus accumbens) effects of mu opioid agonists [Adams et al. (1990) J. Pharmacol. Exp. Ther. 255:1027-1032; Martin et al. (1995) J. Pharmacol. Exp. Ther. 272:1135-1140]. However, the effects of beta-FNA were not equal in all brain regions. This may indicate regional differences in the coupling efficiency of mu opioid receptors with G proteins, or in the effects of beta-FNA on mu opioid receptor binding or on mu opioid receptor-stimulated G protein activity.