heroin and 3-(2-hydroxy-4-(1-1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol

Opioids provide pain relief but are associated with several adverse effects. Researchers are exploring cannabis-based medicine as an alternative. However, little is known about the tendency for physical dependence on cannabinoids in comparison with that on opioids in primates. The aim of this study was to compare the potency of heroin and delta-9-tetrahydrocannabinol (THC) in eliciting analgesic effects and the development of physical dependence between opioids and cannabinoids in both male and female rhesus monkeys. Systemic administration of either heroin (0.03-0.18 mg/kg) or THC (0.3-1.8 mg/kg) in a dose-dependent manner produced antinociceptive effects against an acute thermal nociceptive stimulus. The μ-opioid receptor antagonist naltrexone (0.01 mg/kg) and the cannabinoid receptor antagonist SR141716A (0.3 mg/kg) produced the same degree of rightward shift in the dose-response curves for heroin- and THC-induced antinociception, respectively. Monkeys implanted with telemetry devices were subjected to short-term repeated administrations (two injections per day for 1-3 days) of either heroin (0.18 mg/kg), morphine (1.8 mg/kg), THC (1.8 mg/kg), or CP 55,940 (0.032 mg/kg). Administration of naltrexone (0.01 mg/kg) increased respiration, heart rate, and blood pressure in heroin- or morphine-treated monkeys. In contrast, administration of SR141716A (0.3 mg/kg) did not cause a significant change in these physiological parameters in THC- or CP 55,940-treated monkeys. Additionally, morphine, but not CP 55,940, enhanced the monkeys' hypersensitivity to the algogen capsaicin. Collectively, these results demonstrate that in nonhuman primates, both opioids and cannabinoids exert comparable antinociception; however, physical dependence on opioids, but not cannabinoids, at their antinociceptive doses, occurs following short-term exposures.

Topics: Analgesics, Opioid; Animals; Cannabinoid Receptor Agonists; Cannabinoids; Dose-Response Relationship, Drug; Dronabinol; Female; Heroin; Male; Morphine; Naltrexone; Rimonabant

This study examines the effect of intravenous self-administration (SA) of either heroin or the cannabinoid receptor agonist WIN 55,212-2 on levels and functionality of mu-opioid (MOR) and CB1-cannabinoid receptors (CB1R) in reward-related brain areas, such as the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CP), hippocampus (Hippo), amygdala (Amy), hypothalamus (Hypo) and ventral tegmental area (VTA). [3H]DAMGO and [3H]CP-55,940 autoradiography and agonist-stimulated [35S]GTPgammaS binding were performed on brain sections of rats firmly self-administering heroin or WIN 55,212-2. Animals failing to acquire heroin or cannabinoid SA behaviour as well as drug-naïve animals never exposed to experimental apparatus or procedure (home-control group) were used as controls. With respect to control groups, which displayed very similar values, rats SA heroin showed increased MOR binding in the NAc (+174%), CP (+165%), Hippo (+121%), VTA (+175%), an enhanced CB1R density localized in the Amy (+147%) and VTA (+37%), and a widespread increased CB1 receptor functionality in the PFC (+95%), NAc (+313%), CP (+265%), Hippo (+38%), Amy (+221%). In turn, cannabinoid SA differently modulates CB1R binding in the Amy (+47%), Hypo (+94%), Hippo (-23%), VTA (-15%), and increases MOR levels (PFC: +124%; NAc: +68%; CP: +80%; Hippo: +73%; Amy: +99%) and efficiency (Hippo: +518%; Amy: +173%; Hypo: +188%). These findings suggest that voluntary chronic intake of opioids or cannabinoids induces reciprocal but differential regulation of MORs and CB1Rs density and activity in brain structures underlying drug-taking and drug-seeking behaviour, which could represent long-term neuroadaptations contributing to the development of drug addiction and dependence.

Topics: Analgesics, Opioid; Animals; Benzoxazines; Brain; Cannabinoids; Cyclohexanols; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Guanosine 5'-O-(3-Thiotriphosphate); Heroin; Humans; Male; Morpholines; Naphthalenes; Rats; Receptor, Cannabinoid, CB1; Receptors, Opioid, mu; Self Administration

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

The effect of CP 55,940 [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxypropyl)cyclo-hesanol], heroin and etonitazene on intracerebroventricular (i.c.v.) self-administration in a free-choice procedure was evaluated in rats. Animals were trained in 1-h daily sessions with a continuous reinforcement schedule to press two active levers to obtain the vehicle of each drug. Then, when a stable baseline was reached, each drug could be self-administered by pressing the lever found to be less preferred during training, while the vehicle came from the other. The number of bar pressings associated with the delivery of increasing unit doses of CP 55,940 (0.1, 0.2, 0.4, 0.8, 1.6 microg/2 microl/infusion), heroin (0.125, 0.25, 0.5, 1, 2 microg/2 microl/infusion) or etonitazene (0.1--0.2--0.5--1 microg/ 2 microl/infusion) and with the delivery of the corresponding vehicle was fitted by symmetrical parabolas. The mean drug intake was linearly related to the log of self-administered drugs. Pretreatment with SR141716A [N-piperidino-5-(4-chlorophenyl)1-(2,4-dichloro-phenyl)-4-methylpyrazole-3-carboxamide] (0.5 mg/kg) or naloxone HCl (2 mg/kg/i.p.) 15 min before each daily session reduced the self-administration of both CP 55,940 and heroin. The combination of CP 55,940 with heroin or etonitazene reduced the number of drug-associated lever pressings compared to that obtained with the maximal reinforcing unit dose of each drug alone. These findings suggest there may be a strong interaction between opioids and the cannabinoid system.

Topics: Analgesics; Analgesics, Opioid; Animals; Benzimidazoles; Conditioning, Operant; Cyclohexanols; Heroin; Male; Naloxone; Narcotic Antagonists; Narcotics; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Reinforcement Schedule; Rimonabant; Self Administration

Cannabinoids appear atypical as drugs of abuse since controversial data exist concerning the ability to lower the thresholds for electrical self-stimulation (Stark and Dews, 1980; Gardner et al., 1988; Gardner, 1992) and to support self-administration (Martellotta et al., 1998; Tanda et al., 2000) or conditioned place preference in animals (Lepore et al., 1995; Parker and Gillies, 1995; McGregor et al., 1996; Sañudo-Peña et al., 1997; Chaperon et al., 1998; Hutcheson et al., 1998; Mallet and Beninger, 1998; Cheer et al., 2000; Valjent and Maldonado, 2000). Opioids and cannabinoids share some pharmacological properties (Manzanares et al., 1999). The most interactions were found in antinociception (Welch and Stevens, 1992; Smith et al., 1994) and, to a lesser extent, in drug reinforcement (Chen et al., 1990; Vela et al., 1995; Tanda et al., 1997). In the present study we asked whether: (1) a potent synthetic cannabinoid receptor agonist, [(-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptil)-phenyl]-trans-4-(3-hydroxy propyl) cyclohexanol] (CP 55,940) (from 10 to 40 microg/kg), which binds to the brain cannabinoid receptors with high affinity (Herkenham et al., 1991), would induce conditioned place preference, in comparison with heroin (from 0.1 to 5 mg/kg); (2) what type of receptor was involved; (3) what kind of interaction there was between the two drugs, when given in combination, on reward. CP 55,940 elicited a conditioned place preference only at a dose of 20 microg/kg similar in intensity to that of heroin (2 mg/kg). The reinforcing properties of the cannabinoid agonist were fully antagonised by pretreatment with the brain cannabinoid receptor-1 (CB(1)) antagonist, [N-piperidino-5-(4-chlorophenyl) 1-(2,4-dichloro-phenyl)-4-methyl pyrazole-3-carboxamide hydrochloride] (SR 141716A) and naloxone. The combination of CP 55,940 and heroin, at the reinforcing doses, led to a reward which did not show any additive effect. Taken together these findings are important for understanding how the cannabinoids produce reward and the interconnection of the opioid and cannabinoid system in the motivation.

Topics: Analgesics; Analgesics, Opioid; Animals; Brain; Conditioning, Psychological; Cyclohexanols; Dose-Response Relationship, Drug; Drug Interactions; Heroin; Male; Naloxone; Narcotic Antagonists; Opioid Peptides; Piperidines; Pyrazoles; Rats; Rats, Wistar; Receptors, Cannabinoid; Receptors, Drug; Reward; Rimonabant