piperidines and Heroin-Dependence

From the Aristotelian ancient Greece, pain has been associated with appetites or emotions and is opposite to pleasure. Reward and addiction is also linked to pleasure and compulsive drug seeking reinstates pleasure. Alleviation of chronic pain can induce a euphoric phase similar to what is found in addiction. Both chronic pain and addiction are recognized as a disease of the central nervous system. They share many characteristics and brain regions/mechanisms. Evidence points to the usefulness of cannabinoids as a new class of agents to add to the pharmaceutical toolbox in the management of chronic pain. Wilkerson and colleagues, in this issue, examine SA-57, an inhibitor of two different endocannabinoid catabolic enzymes FAAH and MAGL, demonstrating its analgesic effectiveness and morphine-sparing properties in a chronic pain model, as well as its ability to reduce heroin seeking behavior in a self-administration paradigm in mice. This timely study emphasizes the need for development of more efficacious chronic pain therapeutics with minimized abuse potential and/or reinforcing properties. It also highlights the need for better understanding of the overlapping circuitry of chronic pain, reward, and addiction.

Topics: Amidohydrolases; Analgesics; Animals; Chronic Pain; Endocannabinoids; Heroin Dependence; Mice; Monoacylglycerol Lipases; Piperidines

Persistent relapse to addictive drugs constitutes the most challenging problem in addiction therapy, and is linked to impaired prefrontal cortex regulation of motivated behaviors involving the nucleus accumbens. Using a rat model of heroin addiction, we show that relapse requires long-term potentiation (LTP)-like increases in synaptic strength in the prefrontal cortex projection to the nucleus accumbens. The increased synaptic strength was paralleled by dendritic spine enlargement in accumbens spiny neurons and required up-regulated surface expression of NMDA2b-containing receptors (NR2B). Accordingly, blocking NR2B before reinstating heroin-seeking prevented the induction of LTP-like changes in spine remodeling and synaptic strength, and inhibited heroin relapse. These data show that LTP-like neuroplasticity in prefrontal-accumbens synapses is initiated by NR2B stimulation and strongly contributes to heroin relapse. Moreover, the data reveal NR2B-containing NMDA receptors as a previously unexplored therapeutic target for treating heroin addiction.

Topics: Analysis of Variance; Animals; Biotinylation; Dendrites; Electrophysiology; Extinction, Psychological; Heroin Dependence; Long-Term Potentiation; Microscopy, Confocal; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Recurrence; Self Administration; Synaptic Transmission

As with other drugs of abuse, heroin use is characterized by a high incidence of relapse following detoxification that can be triggered by exposure to conditioned stimuli previously associated with drug availability. Recent findings suggest that cannabinoid CB(1) receptors modulate the motivational properties of heroin-conditioned stimuli that induce relapse behavior. However, the neural substrates through which CB(1) receptors modulate cue-induced heroin seeking have not been elucidated. In this study, we evaluated alterations in cue-induced reinstatement of heroin-seeking behavior produced by infusions of the CB(1) receptor antagonist SR 141716A (0, 0.3 and 3 microg per side) delivered into the prefrontal cortex (PFC), nucleus accumbens (NAC), and basolateral amygdala (BLA) of rats. Results show that following extinction of operant behavior the presentation of a discriminative stimulus conditioned to heroin availability reinstated nonreinforced lever pressing to levels comparable to preextinction levels. Intra-PFC SR 141716A dose-dependently reduced cue-induced reinstatement of heroin seeking, with a significant reduction following the 3 microg per side dose. In the NAC, both SR 141716A doses induced a significant reduction in cue-induced reinstatement, with the highest dose completely blocking the effect of the cue. In contrast, intra-BLA SR 141716A did not alter cue-induced reinstatement of responding while systemic administration of this antagonist (3 mg/kg, i.p.) significantly blocked cue-induced reinstatement in all three-placement groups (BLA, PFC, and NAC). These findings provide new insights into the neural mechanisms through which CB(1) receptors modulate the motivational properties of heroin-associated cues inducing relapse.

Topics: Amygdala; Animals; Conditioning, Operant; Cues; Disease Models, Animal; Dose-Response Relationship, Drug; Extinction, Psychological; Heroin; Heroin Dependence; Male; Motivation; Narcotics; Nucleus Accumbens; Piperidines; Prefrontal Cortex; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Reinforcement, Psychology; Reward; Rimonabant

A 24-year-old female with a history of former heroin addiction underwent open heart surgery for a mechanical tricuspid valve replacement. Anaesthesiological management included a thoracic epidural catheter at the Th(2)/Th(3) segments and balanced general anaesthesia (remifentanil, desflurane/propofol). Additionally, clonidine (2 microg*kg(-1)*h(-1)) was continuously administered. Pain therapy was achieved using 0.375% ropivacaine via a thoracic epidural catheter (4 ml*h(-1)) and metamizole (4 x 1 g/day) intravenously. With this concept we were able to achieve an appropriate anaesthesia and analgesia and the operation was carried out without complications.

Topics: Adrenergic alpha-Agonists; Adult; Amides; Anesthesia, Epidural; Anesthesia, General; Anesthetics, Inhalation; Anesthetics, Intravenous; Anesthetics, Local; Anti-Inflammatory Agents, Non-Steroidal; Clonidine; Desflurane; Dipyrone; Female; Heart Valve Prosthesis Implantation; Heroin Dependence; Humans; Isoflurane; Pain, Postoperative; Piperidines; Propofol; Remifentanil; Ropivacaine; Tricuspid Valve

We recently described a reinstatement procedure that models relapse to drug abuse in cases where abstinence results from aversive consequences of drug use. The potential value of this punishment-based model of relapse depends on its sensitivity to relapse-inducing events that are ineffective in the widely used extinction-based model.. It is known that certain drugs can have anti-punishment effects, but these drugs have not been tested in the punishment-based reinstatement procedure. Therefore, the effects of the benzodiazepine, lorazepam, were examined using punishment-based and extinction-based reinstatement procedures.. Rats self-administered the opioid, remifentanil (4 microg/kg per infusion). Two punishment groups were trained with response-contingent footshock that suppressed baseline rates of responding to zero. In an extinction group, remifentanil delivery was discontinued, and baseline responding stabilized at a low rate (mean=0.06 responses/min). Lorazepam (0.08-10 mg/kg, IP) was given during test sessions with the shock contingency discontinued for both punishment groups. Remifentanil delivery was maintained during testing in one punishment group but not the other.. Lorazepam reinstated self-administration responding in both punishment groups but not in the extinction group. Priming injections of heroin reinstated responding in both the punishment and extinction groups, but combining heroin and lorazepam did not enhance reinstatement.. This is the first demonstration that a trigger for relapse may have different effects depending on whether aversive conditioning contributed to the achievement of abstinence. It may be important to consider potential anti-punishment effects of both abused drugs and therapeutic agents in the treatment of individuals with a history of drug abuse.

Topics: Analgesics, Opioid; Animals; Anti-Anxiety Agents; Conditioning, Operant; Dose-Response Relationship, Drug; Electroshock; Extinction, Psychological; Heroin; Heroin Dependence; Lorazepam; Male; Piperidines; Punishment; Rats; Rats, Sprague-Dawley; Remifentanil; Self Administration; Substance-Related Disorders

Rats with a previous history of heroin self-administration were studied to assess interactions occurring between cannabinoids and opioids in an animal model of reinstatement of heroin-seeking behaviour. Rats were trained to self-administer heroin and after a long-term extinction were primed with one of the following non-contingent non-reinforced drug administrations: saline (or vehicle), heroin, synthetic cannabinoid CB(1) receptor agonists (WIN 55,212-2 or CP 55,940), opioid antagonist (naloxone) or CB(1) antagonist (SR 141716A), alone or in combination. After primings, lever-pressing activity was recorded and compared to those observed during previous phases of training and extinction. Results of this study showed that (i) priming injections of heroin (0.1 mg/kg) as well as CB(1) agonists WIN 55,212-2 (0.15 or 0.30 mg/kg) and CP 55,940 (0.05 or 0.1 mg/kg) completely restore heroin-seeking behaviour; (ii) primings of naloxone (1 mg/kg) and SR 141716A (0.3 mg/kg) had no effect when administered alone; (iii) heroin-induced reinstatement was fully prevented by pre-treatment with either naloxone or SR 141716A; (iv) pre-treatment with SR 141716A significantly reduced WIN 55,212-2 and CP 55,940 priming effects. These results suggest that cannabinoid CB(1) receptors play an important role in the mechanisms underlying relapse to heroin-seeking and depict CB(1) antagonists as possible therapeutic agents for use in the prevention of relapse to heroin abuse.

Topics: Animals; Behavior, Addictive; Benzoxazines; Conditioning, Operant; Cyclohexanols; Drug Interactions; Extinction, Psychological; Heroin; Heroin Dependence; Male; Morpholines; Naloxone; Naphthalenes; Piperidines; Pyrazoles; Rats; Rats, Inbred Strains; Receptor, Cannabinoid, CB1; Rimonabant; Self Administration

Functionality of the endogenous cannabinoid system undergoes relevant changes in reward-related brain areas in animal models of opiate addiction. By using a limited access heroin self-administration paradigm we show that cannabinoid CB(1) receptor antagonist N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 0.03-3.0 mg/kg) suppresses heroin self-administration only in opiate-dependent rats but not in non-dependent animals. These results further support the study of cannabinoid CB(1) receptor antagonists for the treatment of opiate addiction.

Topics: Animals; Cannabinoid Receptor Antagonists; Dose-Response Relationship, Drug; Heroin; Heroin Dependence; Male; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Rimonabant; Self Administration

The present study was designed to explore the relationship between the cannabinoid and opioid receptors in animal models of opioid-induced reinforcement. The acute administration of SR141716A, a selective central cannabinoid CB1 receptor antagonist, blocked heroin self-administration in rats, as well as morphine-induced place preference and morphine self-administration in mice. Morphine-dependent animals injected with SR141716A exhibited a partial opiate-like withdrawal syndrome that had limited consequences on operant responses for food and induced place aversion. These effects were associated with morphine-induced changes in the expression of CB1 receptor mRNA in specific nuclei of the reward circuit, including dorsal caudate putamen, nucleus accumbens, and septum. Additionally, the opioid antagonist naloxone precipitated a mild cannabinoid-like withdrawal syndrome in cannabinoid-dependent rats and blocked cannabinoid self-administration in mice. Neither SR141716A nor naloxone produced any intrinsic effect on these behavioral models. The present results show the existence of a cross-interaction between opioid and cannabinoid systems in behavioral responses related to addiction and open new strategies for the treatment of opiate dependence.

Topics: Animals; Avoidance Learning; Cannabinoids; Caudate Nucleus; Conditioning, Operant; Disease Models, Animal; Heroin; Heroin Dependence; Male; Mice; Morphine; Morphine Dependence; Naloxone; Narcotic Antagonists; Nucleus Accumbens; Piperidines; Putamen; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Receptors, Opioid; Rimonabant; RNA, Messenger; Self Administration; Septum of Brain