piperidines and Opioid-Related-Disorders

Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care.. To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care.. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data.. We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced.. Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE.. We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (. In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.

Topics: Constipation; Defecation; Female; Gastrointestinal Agents; Humans; Intestinal Diseases; Male; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Neoplasms; Opioid-Related Disorders; Oxycodone; Palliative Care; Piperidines; Quaternary Ammonium Compounds; Randomized Controlled Trials as Topic; Receptors, Opioid, mu

Opioid-induced bowel dysfunction (OBD) is characterized by constipation, incomplete evacuation, bloating, and increased gastric reflux. OBD occurs both acutely and chronically, in multiple disease states, resulting in increased morbidity and reduced quality of life.. To compare the efficacy and safety of traditional and peripherally active opioid antagonists versus conventional interventions for OBD.. We searched MEDLINE, the Cochrane Central Register of Controlled Trials and EMBASE in January 2007. Additional reports were identified from the reference lists of retrieved papers.. Studies were included if they were randomized controlled trials that investigated the efficacy of mu-opioid antagonists for OBD.. Data were extracted by two independent review authors and included demographic variables, diagnoses, interventions, efficacy, and adverse events.. Twenty-three studies met inclusion criteria and provided data on 2871 opioid antagonist-treated patients. The opioid antagonists investigated were alvimopan (nine studies), methylnaltrexone (six), naloxone (seven), and nalbuphine (one). Meta-analysis demonstrated that methylnaltrexone and alvimopan were better than placebo in reversing opioid-induced increased gastrointestinal transit time and constipation, and that alvimopan appears to be safe and efficacious in treating postoperative ileus. The incidence of adverse events with opioid antagonists was similar to placebo and generally reported as mild-to-moderate.. Insufficient evidence exists for the safety or efficacy of naloxone or nalbuphine in the treatment of OBD. Long-term efficacy and safety of any of the opioid antagonists is unknown, as is the incidence or nature of rare adverse events. Alvimopan and methylnaltrexone both show promise in treating OBD, but further data will be required to fully assess their place in therapy.

Topics: Constipation; Defecation; Gastrointestinal Agents; Humans; Intestinal Diseases; Nalbuphine; Naloxone; Naltrexone; Narcotic Antagonists; Opioid-Related Disorders; Piperidines; Quaternary Ammonium Compounds; Receptors, Opioid, mu

Ketamine has been used as part of a multimodal analgesia regime in opioid abusers undergoing general anesthesia. We studied the opioid-sparing effect of a very low-dose bolus of ketamine as part of moderate sedation for opioid abuse patients undergoing extracorporeal shock wave lithotripsy.. In this randomized, placebo-controlled clinical trial, 190 opioid abusers were enrolled. They were stratified into 2 blocks based on their daily opioid consumption. Both blocks were then randomized to receive 0.1 mg/kg IV ketamine (group K) or placebo (group P). Lithotripsy was performed under moderate sedation with intermittent bolus doses of remifentanil (0.2 µg/kg) to alleviate pain. The total remifentanil dose (primary outcome) and respiratory adverse events (secondary outcome) were compared in the 2 groups.. Remifentanil administration in the group with low-opioid consumers was 1.6 ± 0.4 µg/kg (group P) compared with 1.0 ± 0.2 µg/kg in group K (confidence interval [CI](of difference) 95%, 0.4-0.7; P < 0.001). Patients who had high-opioid consumption received 2.0 ± 0.5 µg/kg (group P) vs 1.5 ± 0.3 µg/kg (group K) remifentanil (CI(of difference) 95%, 0.40-0.75; P < 0.001). Ready to discharge time was statistically longer in high-consumption opioid abusers who received placebo compared with group K (55 ± 13 minutes vs 44 ± 8 minutes, CI(of difference) 95%, 6-15; P < 0.001). The incidences of bradypnea, apnea, nausea, vomiting, and hemodynamic changes were not statistically different between the ketamine and placebo groups.. Preemptive low-dose ketamine (0.1 mg/kg) as a bolus has opioid-sparing effects in opioid abusers undergoing moderate sedation.

Topics: Adolescent; Adult; Analgesia, Patient-Controlled; Analgesics, Opioid; Anesthetics, Dissociative; Conscious Sedation; Double-Blind Method; Female; Hemodynamics; Humans; Injections, Intravenous; Ketamine; Lithotripsy; Male; Middle Aged; Opioid-Related Disorders; Pain Measurement; Pilot Projects; Piperidines; Postoperative Complications; Postoperative Nausea and Vomiting; Remifentanil; Treatment Outcome; Young Adult

The treatment of acute pain in patients maintained on methadone is difficult due to increased pain sensitivity (hyperalgesia) and cross-tolerance to other opioids. This study aimed to investigate whether remifentanil elicits antinociception in methadone-maintained subjects in a dose-dependent manner. Eight chronic methadone-maintained subjects attended the testing session approximately 20 h after their normal methadone dose (range 50-110 mgday(-1)). Following a 20 min saline infusion, subjects were administered intravenous remifentanil in seven increasing doses ranging from 0.5 to 3.5 microgkg(-1)min(-1), each for 2 0min. Testing was performed in the last 10 min of each infusion. The testing measures included nociception, as measured by the cold pressor test, withdrawal using the subjective opiate withdrawal scale (SOWS), and subjective opioid effects using the morphine-benzedrine group scale (MBG). Results showed dose-dependent increase in cold pressor tolerance time from baseline of 15.6+/-3.5 (mean+/-SEM)s up to 77.3+/-24.7s during this dosing protocol. During the infusion typical mu-opioid receptor agonist side effects were observed, but with no withdrawal. Methadone-maintained patients demonstrate significant tolerance to remifentanil and may require opioid doses 20-30 higher than required for the treatment of acute pain in opioid-naïve patients.

Topics: Adult; Analgesics, Opioid; Cold Temperature; Drug Interactions; Drug Tolerance; Humans; Infusions, Intravenous; Male; Methadone; Opioid-Related Disorders; Pain; Pain Measurement; Piperidines; Remifentanil

Topics: Analgesics, Opioid; Cause of Death; Drug Overdose; Fatal Outcome; Female; Fentanyl; Humans; Imidazoles; Michigan; Middle Aged; Opioid-Related Disorders; Piperidines; Population Surveillance; Synthetic Drugs

The incidence of fatal overdoses has increased worldwide due to the widespread access to illicit fentanyl and its potent analogues. Vaccines offer a promising strategy to reduce the prevalence of opioid use disorders (OUDs) and to prevent toxicity from accidental and deliberate exposure to fentanyl and its derivatives. This study describes the development and characterization of vaccine formulations consisting of novel fentanyl-based haptens conjugated to carrier proteins. Vaccine efficacy was tested against opioid-induced behavior and toxicity in mice and rats challenged with fentanyl and its analogues. Prophylactic vaccination reduced fentanyl- and sufentanil-induced antinociception, respiratory depression, and bradycardia in mice and rats. Therapeutic vaccination also reduced fentanyl intravenous self-administration in rats. Because of their selectivity, vaccines did not interfere with the pharmacological effects of commonly used anesthetics nor with methadone, naloxone, oxycodone, or heroin. These preclinical data support the translation of vaccines as a viable strategy to counteract fentanyl use disorders and toxicity.

Topics: Animals; Bacterial Proteins; Cattle; Diphtheria Toxin; Female; Fentanyl; Haptens; Hemocyanins; Male; Mice, Inbred BALB C; Opioid-Related Disorders; Piperidines; Proof of Concept Study; Rats, Sprague-Dawley; Serum Albumin, Bovine; Sufentanil; Vaccines

Nociceptin/orphanin FQ (NOP) receptor ligands have shown efficacy as putative analgesics and can modulate the abuse-related effects of opioids, suggesting therapeutic applications. The discriminative stimulus effects of a drug are related to their subjective effects, a predictor of abuse potential. To determine whether activation of NOP receptors could alter the subjective effects of an abused opioid analgesic, a novel oxycodone discrimination was established in mice, characterized with positive and negative controls, and its expression evaluated with a NOP receptor agonist.. Adult male C57BL/6 mice were trained to discriminate 1.3 mg/kg oxycodone from vehicle in a two-lever operant procedure. The discrimination was characterized with naloxone challenge, and generalization tests with the μ-opioid receptor agonists, heroin and morphine, and the κ-opioid receptor selective agonist, U50488. Subsequently, effects of the NOP agonist Ro64-6198 were evaluated with and without oxycodone.. Oxycodone generalization occurred in a dose-dependent manner and was reversed by naloxone pretreatment. Heroin and morphine, but not U50488, substituted for oxycodone. Co-treatment of 1 mg/kg Ro64-6198 with the oxycodone training dose reduced % oxycodone lever responding (%OLR) and restored response rates to vehicle control levels. J-113397, a NOP antagonist, reversed these effects. Co-administration of 1 mg/kg Ro64-6198 with a range of oxycodone doses resulted in rightward dose-effect curve shifts in %OLR and response rates compared to oxycodone alone.. These results provide additional evidence that NOP receptor activation can modulate the subjective effects of opioid analgesics and represent the first characterization of oxycodone's discriminative stimulus effects in mice.

Topics: Analgesics, Opioid; Animals; Benzimidazoles; Imidazoles; Ligands; Male; Mice; Mice, Inbred C57BL; Morphine; Naloxone; Nociceptin Receptor; Opioid-Related Disorders; Oxycodone; Piperidines; Receptors, Opioid; Spiro Compounds

Early-life conditions can contribute to the propensity for developing neuropsychiatric disease, including substance abuse disorders. However, the long-lasting mechanisms that shape risk or resilience for drug addiction remain unclear. Previous work has shown that a neonatal handling procedure in rats (which promotes enriched maternal care) attenuates morphine conditioning, reduces morphine-induced glial activation, and increases microglial expression of the anti-inflammatory cytokine interleukin-10 (IL-10). We thus hypothesized that anti-inflammatory signaling may underlie the effects of early-life experience on later-life opioid drug-taking. Here we demonstrate that neonatal handling attenuates intravenous self-administration of the opioid remifentanil in a drug-concentration-dependent manner. Transcriptional profiling of the nucleus accumbens (NAc) from handled rats following repeated exposure to remifentanil reveals a suppression of pro-inflammatory cytokine and chemokine gene expression, consistent with an anti-inflammatory phenotype. To determine if anti-inflammatory signaling alters drug-taking behavior, we administered intracranial injections of plasmid DNA encoding IL-10 (pDNA-IL-10) into the NAc of non-handled rats. We discovered that pDNA-IL-10 treatment reduces remifentanil self-administration in a drug-concentration-dependent manner, similar to the effect of handling. In contrast, neither handling nor pDNA-IL-10 treatment alters self-administration of food or sucrose rewards. These collective observations suggest that neuroimmune signaling mechanisms in the NAc are shaped by early-life experience and may modify motivated behaviors for opioid drugs. Moreover, manipulation of the IL-10 signaling pathway represents a novel approach for influencing opioid reinforcement.

Topics: Analgesics, Opioid; Animals; Animals, Newborn; Conditioning, Operant; Cytokines; Disease Models, Animal; Female; Gene Expression Regulation; Genetic Therapy; Handling, Psychological; Interleukin-10; Male; Mannose; Nucleus Accumbens; Opioid-Related Disorders; Piperidines; Pregnancy; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Remifentanil; Signal Transduction

Opioid abuse is a major problem around the world. Identifying environmental factors that contribute to opioid abuse and addiction is necessary for decreasing this epidemic. In rodents, environmental enrichment protects against the development of low dose stimulant self-administration, but studies examining the effect of enrichment and isolation (compared to standard housing) on the development of intravenous opioid self-administration have not been conducted. The present study investigated the role of environmental enrichment on self-administration of the short-acting μ-opioid remifentanil.. Rats were raised in an enriched condition (Enr), standard condition (Std), or isolated condition (Iso) beginning at 21 days of age and were trained to lever press for 1 or 3 μg/kg/infusion remifentanil in young adulthood. Acquisition of self-administration and responding during increasing fixed ratio requirements were assessed, and a dose-response curve was generated.. Environmental enrichment reduced remifentanil intake, suggesting that social and environmental novelty may protect against opioid abuse.

Topics: Analgesics, Opioid; Animals; Behavior, Addictive; Dose-Response Relationship, Drug; Environment; Infusions, Intravenous; Male; Opioid-Related Disorders; Piperidines; Rats; Rats, Sprague-Dawley; Remifentanil; Self Administration; Treatment Outcome

Medium-sized spiny neurons (MSNs), the predominant neuronal population of the striatum, are an integral component of the many cortical and limbic pathways associated with reward-related behaviors. A differential role of the D1 receptor-enriched (D1) MSNs of the striatonigral direct pathway, as compared with the D2 receptor-enriched (D2) MSNs of the striatopallidal indirect pathway, in mediating the addictive behaviors associated with cocaine is beginning to emerge. However, whether opioids, well-known analgesics with euphoric properties, similarly induce dissociable signaling adaptations in these neurons remains unclear. Transgenic mice expressing green fluorescent protein (GFP)-labeled D1 or D2 neurons were implanted with intravenous jugular catheters. Mice learned to self-administer 0.1mg/kg/infusion of the opioid remifentanil during 2h sessions over 13 contiguous days. Thereafter, the electrophysiological properties of D1- and D2-MSNs in the shell region of the nucleus accumbens (NAc) were assessed. We found that prior opioid exposure did not alter the basic membrane properties nor the kinetics or amplitude of miniature excitatory postsynaptic currents (mEPSCs). However, when challenged with the mu opioid receptor (μOR) agonist DAMGO, the characteristic inhibitory profile of this receptor was altered. DAMGO inhibited the frequency of mEPSCs in D1-MSNs from control mice receiving saline and in D2-MSNs from mice exposed to remifentanil or saline, but this inhibitory profile was reduced in D1-MSNs from mice receiving remifentanil. Remifentanil exposure also altered the probability of glutamate release onto D1-, but not D2-MSNs. Together these results suggest a D1-pathway specific effect associated with the acquisition of opioid-seeking behaviors.

Topics: Animals; Corpus Striatum; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Excitatory Postsynaptic Potentials; Female; GABAergic Neurons; Glutamic Acid; Green Fluorescent Proteins; Male; Membrane Potentials; Mice, Transgenic; Narcotics; Nucleus Accumbens; Opioid-Related Disorders; Piperidines; Receptors, Opioid, mu; Remifentanil; Self Administration

Drug abuse can be conceptualized as excessive choice of drug over other reinforcers, and factors that affect drug taking can be examined experimentally using choice procedures. This study examined the impact of reinforcer delay on self-administration of the μ-opioid receptor agonist remifentanil in rhesus monkeys (n = 4) lever pressing under a concurrent fixed-ratio 30 schedule. Responding on either lever delivered an intravenous infusion of either remifentanil or saline. Dose-effect curves were first determined when responding on one lever delivered remifentanil and responding on a second lever delivered saline. Monkeys then chose between two doses of remifentanil, and delay to delivery of the large dose was varied systematically. Responding for remifentanil (0.01-1.0 µg/kg/infusion) increased dose-dependently when the alternative was saline or a dose of remifentanil. Delaying delivery of the large dose of remifentanil by 30, 60, 120, or 240 seconds increased responding for smaller, immediately available doses (0.01-0.1 µg/kg/infusion) and, in some cases, increased responding for doses of remifentanil that did not maintain responding when the alternative was saline. These data demonstrate that delaying the delivery of an opioid receptor agonist can significantly affect its reinforcing effectiveness. The imposition of a delay reduces the effectiveness of large doses of drug to maintain responding and increases the effectiveness of immediately available commodities, including smaller doses of drug. Increased reinforcing effectiveness of smaller doses of drug in the context of other delayed reinforcers might contribute to the development and maintenance of opioid abuse.

Topics: Analgesics, Opioid; Animals; Choice Behavior; Conditioning, Operant; Dose-Response Relationship, Drug; Female; Infusions, Intravenous; Macaca mulatta; Male; Opioid-Related Disorders; Piperidines; Remifentanil; Self Administration

The mGlu5 receptor (mGluR5) has been implicated in the rewarding effect of various drugs of abuse and drug-seeking behaviour. In the present study we investigated the impact of antagonism of mGluR5 with the selective negative allosteric, modulator 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on operant self-administration of morphine as well as cue-induced drug-seeking in adult CD1 mice. Administration of MTEP (20 mg/kg, i.p.) attenuated operant responding for morphine (0.1 mg/kg/infusion) and cue-induced morphine-seeking after a period of forced abstinence. Collectively, these data implicate mGluR5 in the reinforcing effects of opiates and support the proposition that mGluR5 is a potential therapeutic target for treatment of drug addiction.

Topics: Analgesics, Opioid; Analysis of Variance; Animals; Conditioning, Operant; Cues; Dose-Response Relationship, Drug; Injections, Intravenous; Male; Mice; Morphine; Motor Activity; Narcotics; Opioid-Related Disorders; Piperidines; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate; Reinforcement, Psychology; Self Administration; Substance Abuse, Intravenous; Thiazoles

Rodent models of abuse potential are considered to represent a false positive with respect to the low risk of abuse liability associated with the atypical opioid analgesic tramadol. This may reflect either the predictive limitations of the models used to formulate this proposition (drug discrimination and conditioned place preference) or the predictive ability of the rodent per se. To address this concern, we used the rat self-administration model to examine the reinforcing properties of tramadol (0.3-3mg/kg/infusion) under fixed (FR) and progressive-ratio (PR) schedules of reinforcement. Comparisons were made with the typical opioid analgesics morphine (0.03-0.3mg/kg/infusion) and remifentanil (0.001-0.03mg/kg/infusion). All three compounds maintained responding under an FR3 schedule of reinforcement, although clear differences were observed in the rates of responding between compounds. Under a PR schedule, morphine and remifentanil maintained comparable break points, while break points for tramadol did not differ from vehicle. Thus, when examined in the self-administration model, tramadol acts as a relatively weak reinforcer in rodents. These data are consistent with the low risk of tramadol abuse liability in humans and highlight the value of using multiple abuse potential models for assessing abuse liability.

Topics: Analgesics, Opioid; Animals; Conditioning, Operant; Dose-Response Relationship, Drug; Male; Morphine; Opioid-Related Disorders; Piperidines; Rats; Receptors, Opioid, mu; Reinforcement Schedule; Remifentanil; Self Administration; Tramadol

We previously reported the synthesis of three new opioid agonists as well as their in vitro and in vivo activity [Girón, R., Abalo, R., Goicoechea, C., Martín, M.I., Callado, L.F., Cano, C., Goya, P., Jagerovic, N. 2002. Synthesis and opioid activity of new fentanyl analogs. Life Sci. 71, 1023-1034]. One of them, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (IQMF-4), showed an interesting antinociceptive activity. Intraperitoneally (i.p.) administered, it was as effective as fentanyl or morphine, being less potent than fentanyl but more so than morphine. The aim of the present work was to evaluate its antinociceptive effect by different routes of administration, using the hot plate test, and to investigate possible side effects, such as tolerance and withdrawal, in vitro, using the myenteric plexus-longitudinal muscle strip preparation from guinea pig ileum, and in vivo, using the hot plate test. IQMF-4 was more potent than morphine when administered per os (p.o.), but less potent when administered intracerebroventricularly (i.c.v.). By both routes, fentanyl is more potent that IQMF-4. When IQMF-4 was administered i.p., naloxone methiodide, a peripherally acting antagonist, was able to completely block its antinociceptive effect, whereas, after i.c.v. administration, the blockade was only partial. An interesting feature of the new compound is that it induces tolerance in vitro but not in vivo. Moreover, though in vitro withdrawal was not different from fentanyl or morphine, in vivo withdrawal symptoms were significantly less frequent in mice treated with IQMF-4 than in those treated with morphine or fentanyl. Although more assays are required, these results show that IQMF-4 appears to be a potent analgesic compound with an interesting peripheral component, and reduced ability to induce dependence.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Fentanyl; Guinea Pigs; Hot Temperature; Ileum; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Measurement; Pain Threshold; Piperidines; Propane; Quaternary Ammonium Compounds; Reaction Time; Substance Withdrawal Syndrome; Time Factors

Abuse of mixtures of stimulants and opioids ("speedball") is common. Although this combination has been studied in the laboratory, conclusions about the nature of the cocaine/opioid interaction have been mixed.. The objectives of the present experiment were to allow monkeys to self-administer mixtures of cocaine and the mu opioid agonist remifentanil and to quantify the interaction using the isobolographic approach. Our hypothesis was that the drugs would be super-additive in their reinforcing effects.. Rhesus monkeys (n = 5) prepared with i.v. catheters were allowed to self-administer cocaine or saline under a progressive-ratio schedule. When responding was stable, doses of cocaine or remifentanil were made available in test sessions. Next, mixtures of doses of the drugs were tested over a range of doses in 1:1, 1:2, and 2:1 ratios of their ED(50)s. Results were analyzed using isobolographic techniques.. Both drugs alone and all drug mixtures functioned as positive reinforcers in a dose-related manner. Cocaine maintained more responding at maximum than did remifentanil, i.e., was a stronger reinforcer. The experimentally determined equi-effective dose for the 1:1 and 1:2 cocaine/remifentanil mixtures tended toward super-additivity, but the difference from additivity did not achieve statistical significance. The 2:1 mixture was super-additive. Maximum responding maintained by the mixtures was higher than that maintained by remifentanil but not different from cocaine.. Combinations of cocaine and remifentanil can be additive or super-additive as positive reinforcers, depending on proportions of each. Interactions between stimulants and opioids may contribute to the abuse of these mixtures.

Topics: Analgesics, Opioid; Animals; Cocaine; Cocaine-Related Disorders; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Drug Combinations; Macaca mulatta; Male; Opioid-Related Disorders; Piperidines; Regression Analysis; Remifentanil; Self Administration; Substance-Related Disorders

Studies implicate endocannabinoids in the acute and chronic actions of opioid drugs, including the genesis of physical dependence. Previous evidence suggests that spinal release of calcitonin gene-related peptide (CGRP) and activation of its receptors contribute to opioid physical dependence. The release of CGRP at the spinal level is modulated by cannabinoid (CB1)-receptors. Thus, this study examined whether CB1-receptor activity mediates changes in CGRP underlying development of opioid physical dependence. Systemic morphine administration for 5-days elevated CGRP-immunoreactivity in the rat spinal dorsal horn. In situ hybridization of dorsal root ganglion (DRG) neurons revealed an increase in CGRP mRNA during initial (day 1-3) but not later phase (day 4-5) of morphine treatment. CGRP-immunoreactivity in DRG neurons, however, was increased in the later phase of morphine treatment. Naloxone challenge to morphine-treated animals precipitated an intense withdrawal syndrome that depleted CGRP-immunoreactivity and increased Fos expression in the dorsal horn. The Fos-response primarily occurred in neurons that expressed CGRP receptor component protein (RCP) suggesting CGRP activity contributes to neuronal activation during precipitated withdrawal. Spinal slices obtained from morphine-treated animals showed higher levels of CGRP release than from saline controls. Intrathecal co-administration of CB1-receptor antagonists, AM-251 or SR141716A, with daily morphine attenuated the behavioral manifestations of withdrawal. Treatment with AM-251 also reduced the depletion of CGRP, suppressed Fos-induction, and prevented the increase in capsaicin-evoked spinal CGRP release. Altogether, this study suggests that endocannabinoid activity, expressed via CB1-receptors, contributes to the induction of opioid physical dependence through spinal modulation of CGRP.

Topics: Animals; Calcitonin Gene-Related Peptide; Cannabinoid Receptor Modulators; Cannabinoids; Capsaicin; Drug Administration Schedule; Endocannabinoids; Ganglia, Spinal; Hot Temperature; Immunologic Techniques; Male; Morphine; Naloxone; Narcotic Antagonists; Neurons; Nociceptors; Opioid-Related Disorders; Piperidines; Proto-Oncogene Proteins c-fos; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; RNA, Messenger; Spinal Cord; Substance Withdrawal Syndrome

Several compounds, mainly opioid agonists such as methadone, are currently used for long term medication of heroin addicts. Nevertheless, these maintenance treatments have the disadvantage to induce a dependence to another opiate. As interactions between opioid and cannabinoid systems have been demonstrated, the ability of the CB(1) antagonist, SR141716A to reduce morphine-induced addiction was investigated. The effects of SR141716A on the rewarding responses of morphine were evaluated in the place conditioning paradigm. No significant conditioned preference or aversion were observed after repeated treatment with the CB(1) antagonist alone. However, SR141716A was able to antagonize the acquisition of morphine-induced conditioned place preference. SR141716A was co-administered with morphine for 5 days, and the withdrawal syndrome was precipitated by naloxone administration. A reduction in the incidence of two main signs of abstinence: wet dog shakes and jumping was observed while the other were not significantly modified. In contrast, an acute injection of the CB(1) antagonist just before naloxone administration was unable to modify the incidence of the behavioural manifestations of the withdrawal, suggesting that only chronic blockade of CB(1) receptors is able to reduce morphine-induced physical dependence. Several biochemical mechanisms could explain the reduction of opioid dependence by CB(1) antagonists. Whatever the hypotheses, this study supports the reported interaction between the endogenous cannabinoid and opioid systems, and suggests that SR 141716A warrants further investigations for a possible use in opioid addiction.

Topics: Animals; Brain Chemistry; Cannabinoids; Conditioning, Operant; Dynorphins; Male; Mice; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Piperidines; Pyrazoles; Radioimmunoassay; Receptors, Cannabinoid; Receptors, Drug; Receptors, Opioid, kappa; Rimonabant; Substance Withdrawal Syndrome; Synapses

Topics: History, 16th Century; History, 19th Century; Loperamide; Opioid-Related Disorders; Opium; Piperidines