Abstract
Rationale
Many behavioral effects of delta-9-tetrahydrocannabinol (THC), including its discriminative-stimulus effects, are modulated by endogenous opioid systems.
Objective
To investigate opioid receptor subtypes involved in the discriminative effects of THC.
Methods
Rats trained to discriminate 3 mg/kg i.p. of THC from vehicle using a two-lever operant drug-discrimination procedure, were tested with compounds that bind preferentially or selectively to either mu-, delta- or kappa-opioid receptors.
Results
The preferential mu-opioid receptor agonist heroin (0.3–1.0 mg/kg, i.p.), the selective delta-opioid receptor agonist SNC-80 (1–10 mg/kg, i.p.) and the selective kappa-opioid receptor agonist U50488 (1–10 mg/kg, i.p.) did not produce generalization to the discriminative effects of THC when given alone. However, heroin, but not SNC-80 or U50488, significantly shifted the dose–response curve for THC discrimination to the left. Also, the preferential mu-opioid receptor antagonist naltrexone (0.1–1 mg/kg, i.p.), the selective delta-opioid receptor antagonist, naltrindole (1–10 mg/kg, i.p.) and the kappa-opioid receptor antagonist nor-binaltorphimine (n-BNI, 5 mg/kg, s.c.), did not significantly reduce the discriminative effects of the training dose of THC. However, naltrexone, but not naltrindole or n-BNI, significantly shifted the dose–response curve for THC discrimination to the right. Finally, naltrexone, but not naltrindole or n-BNI, blocked the leftward shift in the dose–response curve for THC discrimination produced by heroin.
Conclusions
mu- but not delta- or kappa-opioid receptors are involved in the discriminative effects of THC. Given the role that mu-opioid receptors play in THC’s rewarding effects, the present findings suggest that discriminative-stimulus effects and rewarding effects of THC involve similar neural mechanisms.
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References
Ameri A. (1999) The effects of cannabinoids on the brain. Prog Neurobiol 58(4):315–348
Barrett RL, Wiley JL, Balster RL, Martin BR (1995) Pharmacological specificity of delta 9-tetrahydrocannabinol discrimination in rats. Psychopharmacology 118:419–424
Bilsky EJ, Calderon SN, Wang T, Bernstein RN, Davis P, Hruby VJ, McNutt RW, Rothman RB, Rice KC, Porreca F (1995) SNC 80, a selective, nonpeptidic and systemically active opioid delta agonist. J Pharmacol Exp Ther 273:359–366
Browne RG, Weissman A (1981) Discriminative stimulus properties of delta 9-tetrahydrocannabinol: mechanistic studies. J Clin Pharmacol 21:227S–234S
Castane A, Robledo P, Matifas A, Kieffer BL, Maldonado R (2003) Cannabinoid withdrawal syndrome is reduced in double mu and delta opioid receptor knockout mice. Eur J Neurosci 17:155–159
Chen JP, Paredes W, Li J, Smith D, Lowinson J, Gardner EL (1990) Delta 9-tetrahydrocannabinol produces naloxone-blockable enhancement of presynaptic basal dopamine efflux in nucleus accumbens of conscious, freely-moving rats as measured by intracerebral microdialysis. Psychopharmacology 102:156–162
Clark JA, Pasternak GW (1988) U50,488: a kappa-selective agent with poor affinity for mu1 opiate binding sites. Neuropharmacology 27:331–332
Colpaert FC (1999) Drug discrimination in neurobiology. Pharmacol Biochem Behav 64:337–345
Colpaert FC (2003) Discovering risperidone: the LSD model of psychopathology. Nat Rev, Drug Discov 2:315–320
Devine DP, Wise RA (1994) Self-administration of morphine, DAMGO, and DPDPE into the ventral tegmental area of rats. J Neurosci 14:1978–1984
De Vries TJ, Shippenberg TS (2002) Neural systems underlying opiate addiction. J Neurosci 22:3321–3325
Gardner EL, Lowinson JH (1991) Marijuana’s interaction with brain reward systems: update 1991. Pharmacol Biochem Behav 40:571–580
Ghozland S, Matthes HW, Simonin F, Filliol D, Kieffer BL, Maldonado R (2002) Motivational effects of cannabinoids are mediated by mu-opioid and kappa-opioid receptors. J Neurosci 22:1146–1154
Goldstein A, Naidu A (1989) Multiple opioid receptors: ligand selectivity profiles and binding site signatures. Mol Pharmacol 36:265–272
Herz A (1997) Endogenous opioid systems and alcohol addiction. Psychopharmacology 129:99–111
Holtzman SG (1985) Drug discrimination studies. Drug Alcohol Depend 14:263–282
Jarbe TU, Henriksson BG (1974) Discriminative response control produced with hashish, tetrahydrocannabinols (delta 8-THC and delta 9-THC), and other drugs. Psychopharmacologia 40:1–16
Jarbe TU, Ohlin GC (1977) Stimulus effects of delta(9)-THC and its interaction with naltrexone and catecholamine blockers in rats. Psychopharmacology 54:193–195
Justinova Z, Tanda G, Munzar P, Goldberg SR (2004) The opioid antagonist naltrexone reduces the reinforcing effects of Delta 9 tetrahydrocannabinol (THC) in squirrel monkeys. Psychopharmacology 173:186–194
Kamendulis LM, Brzezinski MR, Pindel EV, Bosron WF, Dean RA (1996) Metabolism of cocaine and heroin is catalyzed by the same human liver carboxylesterases. J Pharmacol Exp Ther 279:713–717
Kamien JB, Bickel WK, Hughes JR, Higgins ST, Smith BJ (1993) Drug discrimination by humans compared to nonhumans: current status and future directions. Psychopharmacology 111:259–270
Kieffer BL, Gaveriaux-Ruff C (2002) Exploring the opioid system by gene knockout. Prog Neurobiol 66:285–306
Maldonado R (2002) Study of cannabinoid dependence in animals. Pharmacol Ther 95:153–164
Maldonado R, Rodriguez de Fonseca F (2002) Cannabinoid addiction: behavioral models and neural correlates. J Neurosci 22:3326–3331
Maldonado R, Valverde O (2003) Participation of the opioid system in cannabinoid-induced antinociception and emotional-like responses. Eur Neuropsychopharmacol 13:401–410
Mansour A, Fox CA, Akil H, Watson SJ (1995) Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications. Trends Neurosci 18:22–29
Manzanares J, Corchero J, Romero J, Fernandez-Ruiz JJ, Ramos JA, Fuentes JA (1999) Pharmacological and biochemical interactions between opioids and cannabinoids. Trends Pharmacol Sci 20:287–294
Mello NK, Negus SS (1996) Preclinical evaluation of pharmacotherapies for treatment of cocaine and opioid abuse using drug self-administration procedures. Neuropsychopharmacology 14:375–424
Navarro M, Carrera MR, Fratta W, Valverde O, Cossu G, Fattore L, Chowen JA, Gomez R, del Arco I, Villanua MA, Maldonado R, Koob GF, Rodriguez de Fonseca F (2001) Functional interaction between opioid and cannabinoid receptors in drug self-administration. J Neurosci 21:5344–5350
Portoghese PS, Lipkowski AW, Takemori AE (1987) Binaltorphimine and nor-binaltorphimine, potent and selective kappa-opioid receptor antagonists. Life Sci 40:1287–1292
Prescott WR, Gold LH, Martin BR (1992) Evidence for separate neuronal mechanisms for the discriminative stimulus and catalepsy induced by delta 9-THC in the rat. Psychopharmacology 107:117–124
Schuster CR, Johanson CE (1988) Relationship between the discriminative stimulus properties and subjective effects of drugs. Psychopharmacol Ser 4:161–175
Shippenberg T, Herz A (1987) Motivational properties of opioids. Pol J Pharmacol Pharm 39:577–583
Solinas M, Panlilio LV, Antoniou K, Pappas LA, Goldberg SR (2003) The cannabinoid CB1 antagonist N-piperidinyl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole-3-carboxamide (SR-141716A) differentially alters the reinforcing effects of heroin under continuous reinforcement, fixed ratio, and progressive ratio schedules of drug self-administration in rats. J Pharmacol Exp Ther 306:93–102
Solinas M, Zangen A, Thiriet N, SR Goldberg (2004) β-Endorphin elevations in the ventral tegmental area regulate the discriminative effects of delta-9-tetrahydrocannabinol. Eur J Neurosci 19:3183–3192
Spanagel R (1996) The influence of opioid antagonists on the discriminative stimulus effects of ethanol. Pharmacol Biochem Behav 54:645–649
Spanagel R, Almeida OF, Shippenberg TS (1994) Evidence that nor-binaltorphimine can function as an antagonist at multiple opioid receptor subtypes. Eur J Pharmacol 264:157–162
Stolerman I (1992) Drugs of abuse: behavioural principles, methods and terms. Trends Pharmacol Sci 13:170–176
Tanda G, Goldberg SR (2003) Cannabinoids: reward, dependence, and underlying neurochemical mechanisms—a review of recent preclinical data. Psychopharmacology 169:115–134
Tanda G, Pontieri FE, Di Chiara G (1997) Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science 276:2048–2050
van Ree JM, Gerrits MA, Vanderschuren LJ (1999) Opioids, reward and addiction: an encounter of biology, psychology, and medicine. Pharmacol Rev 51:341–396
Wiley JL (1999) Cannabis: discrimination of “internal bliss”? Pharmacol Biochem Behav 64:257–260
Wiley JL, Lowe JA, Balster RL, Martin BR (1995) Antagonism of the discriminative stimulus effects of delta 9-tetrahydrocannabinol in rats and rhesus monkeys. J Pharmacol Exp Ther 275:1–6
Yamamura MS, Horvath R, Toth G, Otvos F, Malatynska E, Knapp RJ, Porreca F, Hruby VJ, Yamamura HI (1992) Characterization of [3H]naltrindole binding to delta opioid receptors in rat brain. Life Sci 50:PL119–PL124
Zimmer A, Valjent E, Konig M, Zimmer AM, Robledo P, Hahn H, Valverde O, Maldonado R (2001) Absence of delta-9-tetrahydrocannabinol dysphoric effects in dynorphin-deficient mice. J Neurosci 21:9499–9505
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The authors want to thank C. Wertheim for her excellent technical assistance and G. Tanda for helpful comments on the manuscript.
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Solinas, M., Goldberg, S.R. Involvement of mu-, delta- and kappa-opioid receptor subtypes in the discriminative-stimulus effects of delta-9-tetrahydrocannabinol (THC) in rats. Psychopharmacology 179, 804–812 (2005). https://doi.org/10.1007/s00213-004-2118-x
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DOI: https://doi.org/10.1007/s00213-004-2118-x