The crucial role of nociceptin opioid peptide (NOP) receptor in attenuating relapse to morphine/methamphetamine (poly-drug) addiction in mice

A combination of buprenorphine/naltrexone treatment had been proven to successfully attenuate relapse (reinstatement) to morphine/methamphetamine (poly-drug) addiction in mice using a conditioned place preference (CPP) model. This treatment combination exhibits a mixed opioid receptor pharmacological activities (mu/kappa antagonist and partial NOP agonist). Thus, this recent study aimed to investigate the independent role of the NOP receptor in attenuating relapse to this poly-drug addiction. The male Swiss albino mice were made dependent on 7.5 mg/kg morphine/1.0 mg/kg methamphetamine (poly-drug). The mice were injected with SB 612111 (a selective NOP antagonist) during reinstatement phase, 30 minutes before the administration of0.3 mg/kg buprenorphine/1.0 mg/kg naltrexone combination. The priming dose of poly-drug (2.5 mg/kg morphine/1.0 mg/kg methamphetamine) were given 10 minutes later. The percentage of time spent at the drug-paired compartment was compared with the control group (did not receive SB 612111 treatment). The results revealed that the relapse to poly-drug addiction happened in the group of mice that received SB 612111 prior to buprenorphine/naltrexone (53.81 ± 11.23 %, n = 6). This result was significantly different compared to its own baseline (before the mice were made dependent on poly-drug [-5.37 ± 6.42 %, n = 9, p < 0.05]). In contrast, relapse was significantly attenuated (reduced) in the group of mice that did not receive SB 612111 prior to buprenorphine/naltrexone (19.14 ± 16.89 %, n = 5). The percentage of time spent at the drug-paired compartment was found to be not significantly different compared to its own baseline (-16.14 ± 4.81 %, n = 13). The result suggests that an agonist activity at the NOP receptor is crucial in attenuating relapse to morphine/methamphetamine (poly-drug) addiction. Hence, further investigation needs to be done to evaluate the involvement of this receptor at the brain level

Kappa antagonist to prevent drug relapse: does stage in addiction cycle matter?

Introduction: An upregulation of the kappa opioid receptor (KOR) system during preoccupation stage in addiction cycle will cause dysphoria among addicts which can lead to relapse. Therefore, KOR antagonism might hold the key to prevent relapse. In this study, we aim to identify the exact addiction's stage in which KOR antagonist can be given. Methods: Using a conditioned place preference (CPP) model, adult Swiss albino mice were divided into two major groups. The first group received treatment at the initial stage of morphine withdrawal (7.5 mg/kg. i.p) while the second group received treatment after complete abstinence was achieved. Each major groups were further divided into two treatment groups (n=8-12), either received a functional KOR antagonist (0.3 mg/kg buprenorphine/ 1mg/kg naltrexone combination, i.p) or a selective KOR antagonist (10 mg/kg nor-BNI, i.p) prior to morphine priming (2.5 mg/kg, i.p). All data were analyzed using paired sample t-test. Results: The results showed that relapse was successfully attenuated in the groups that received KOR antagonists only after complete abstinence was successfully achieved (not significantly different from their baseline). However, the mice developed unusual sign of behavior sensitization (intermittent freezing, licking) when buprenorphine/naltrexone combination was given at initial stage of withdrawal. Conclusion: Our initial findings suggest that KOR antagonism might be beneficial only after the addicts achieved complete abstinence to prevent future drug-induced relapse. Brain study should be conducted to explain the unusual behavior seen when the drug intervention is given at an earlier stage of withdrawal

The distinct role of kappa opioid receptor in attenuating relapse to morphine/methamphetamine (polydrug) dependence in mice

A Combination of 0.3mg/kg buprenorphine and 1.0 mg/kg naltrexone treatment shows a promising result due to its ability to attenuate reinstatement (relapse) in morphine/methamphetamine (polydrug)-dependent mice in a conditioned place preference (CPP) model. This prompted us to identify which opioid receptor that contributes to its anti-relapse activity. Using the same CPP model, 10 mg/kg nor- BNI (a selective kappa opioid receptor [KOR] antagonist) was used to evaluate the involvement of KOR in mediating relapse to polydrug dependence. By applying the immunohistochemistry (IHC) technique, the investigation was extended to the mice brain using KOR antibody (EPR18881), focusing on the brain regions that are abundant in KOR density. The results showed that nor-BNI alone failed to attenuate relapse to polydrug dependence. However, the IHC results proved that the number of KOR significantly increased in the striatum during reinstatement compared to post-conditioning (p <0.05). The KOR was significantly suppressed in the treatment group which strengthens the findings from previous studies proving that the KOR plays an important role in mediating relapse to polydrug dependence

The crucial roles of nociceptin opioid peptide (NOP) receptor in attenuating relapse in morphine/methamphetamine (poly-drug) dependence model

BACKGROUND: Effective treatment for relapse prevention to poly-drug is still not yet available although this public health issue is alarming. Our previous study has proved that a combination of buprenorphine/naltrexone treatment successfully attenuated relapse (reinstatement) in morphine/methamphetamine (poly-drug) dependent mice using a conditioned place preference (CPP) model. The net pharmacological effects of buprenorphine/naltrexone treatment combination are agonism at the kappa opioid receptor and a partial agonist at the NOP receptor. Thus, this recent study aimed to investigate if the NOP receptor is the key opioid receptor that is responsible in attenuating relapse to this poly-drug addiction. METHOD: The previous CPP protocol was maintained. The male Swill albino mice were injected with 6.0 mg/kg SB 612111 (a selective NOP antagonist) 30 minutes prior to the administration of the same dose of buprenorphine/naltrexone combination (0.3 mg/kg morphine and 1.0 mg/kg, respectively). The priming doses of poly-drug (2.5 mg/kg morphine/1.0 mg/kg methamphetamine) were given 10 minutes after. The percentage of time spent at the drug-paired compartment was compared between groups. RESULTS: The results revealed that the priming doses of poly-drug induced relapse in the group of mice that received SB 612111 prior to buprenorphine/naltrexone treatment (53.81 ± 11.23 %, n = 6) which was significantly different compared to its baseline (-5.37 ± 6.41 %, n = 9, p < 0.05). In contrast, relapse was significantly attenuated in the group of mice that only received buprenorphine/naltrexone treatment prior to drug priming (19.14 ± 16.89 %, n = 5) which was not significantly different from its baseline (-16.14 ± 4.81 %, n = 13). CONCLUSION: From these results, it is suggested that an agonist activity at the NOP receptor is crucial in preventing relapse to morphine/methamphetamine (poly-drug) dependence. Hence, further investigation needs to be done to evaluate the involvement of this receptor at the brain level

Upregulation of kappa opioid receptor system and its association with relapse to morphine/methamphetamine (poly-drug) addiction

The kappa opioid receptor (KOR) system has been linked to many types of drug addiction. An upregulation of the KOR leads to negative reinforcement effects which might contribute to drug relapse. Previously, our study has shown that a treatment combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg methamphetamine (a partial nociceptin opioid peptide [NOP] agonist and mu/kappa antagonists) has successfully attenuated relapse in morphine/methamphetamine (poly-drug)-dependent mice using a conditioned place preference (CPP) model. Therefore, this recent research work aimed to further investigate the involvement of the KOR system in poly-drug relapse at the brain level. The CPP test procedure was repeated where the mice were conditioned with poly-drug (7.5 mg/kg morphine and 1.0 mg/kg methamphetamine). Following CPP test, the investigation was extended at the brain level by using an immunohistochemistry (IHC) technique. Rabbit monoclonal (EPR 18881) was used as it will bind specifically at the KOR. The level of the KOR is determined at two different stages of addiction; the post-conditioning (dependence) phase and reinstatement (relapse) phase. Four brain regions that have high expression of the KOR and involved in addiction circuits have been selected to be investigated. A significant increment of the KOR expression was seen in striatum during reinstatement compared to post-conditioning (33.39 ± 5.60 % and 16.73 ± 5.27 % respectively, p < 0.05, n = 12). While a significant reduction of the KOR expression during reinstatement compared to post-conditioning observed in the prefrontal cortex (35.07 ± 3.51 % and 44.09 ± 1.78 respectively, p < 0.01, n = 12), no significant changes were detected in hippocampus and amygdala. Surprisingly, the KOR was not affected in amygdala which regulates emotion. The KOR upregulation seen in the striatum suggests that this brain region might be triggered in order to oppose the stimulus-related reaction caused by this poly-drug

Carpaine Promotes Proliferation and Repair of H9c2 Cardiomyocytes after Oxidative Insults

Carpaine has long been identified as the major alkaloid in Carica papaya leaves that possess muscle relaxant properties. Limited study on the molecular signaling properties of carpaine urges us to conduct this study that aims to elucidate the mechanism underlying the cardioprotective effect of carpaine in embryonic cardiomyocytes of the H9c2 cell line. The 50% inhibitory concentration (IC50) of carpaine was first determined using a colorimetric MTT assay to establish the minimum inhibitory concentration for the subsequent test. Using a 1 &micro;M carpaine treatment, a significant increase in the H9c2 proliferation rate was observed following 24 and 48 h of incubation. A Western blot analysis also revealed that carpaine promotes the upregulation of the cell cycle marker proteins cyclin D1 and PCNA. Carpaine-induced H9c2 cell proliferation is mediated by the activation of the FAK-ERK1/2 and FAK-AKT signaling pathways. In the setting of ischemia-reperfusion injury (IRI), carpaine provided a significant protective role to recover the wounded area affected by the hydrogen peroxide (H2O2) treatment. Furthermore, the oxidative-stress-induced reduction in mitochondrial membrane potential (MMP) and overproduction of reactive oxygen species (ROS) were attenuated by carpaine treatment. The current study revealed a novel therapeutic potential of carpaine in promoting in vitro cardiomyocyte proliferation and repair following injury

Distinct role of kappa opioid receptor in attenuating relapse to morphine/methamphetamine (polydrug) dependence

A combination of 0.3 mg/kg buprenorphine and 1.0 mg/kg naltrexone treatment shows a promising result due to its ability to attenuate reinstatement (relapse) in morphine/methamphetamine (polydrug)-dependent mice in a conditioned place preference (CPP) model. This prompted us to identify which opioid receptor that contributes to its anti-relapse activity. Using the same CPP model, 10 mg/kg nor-BNI (a selective kappa opioid receptor [KOR] antagonist) was used to evaluate the involvement of KOR in mediating relapse to polydrug dependence. By applying the immunohistochemistry (IHC) technique, the investigation was extended to the mice brain using KOR antibody (EPR18881), focusing on the brain regions that are abundant in KOR density. The results showed that nor-BNI alone failed to attenuate relapse to polydrug dependence. However, the IHC results proved that the number of KOR significantly increased in the striatum during reinstatement compared to post-conditioning (p <0.05). The KOR was significantly suppressed in the treatment group which strengthens the findings from the previous studies proving that the KOR plays an important role in mediating relapse to polydrug dependence