title: Cross-sensitization and cross-tolerance between exogenous cannabinoid antinociception and endocannabinoid-mediated stress-induced analgesia.
abstract: Footshock stress induces both endocannabinoid mobilization and antinociception. The present studies investigated behavioral plasticity in cannabinoid antinociceptive mechanisms following repeated activation using the tail-flick test. A secondary objective was to ascertain whether blockade of stress antinociception by the CB(1) antagonist rimonabant could be attributed to changes in locomotor activity. The cannabinoid agonist WIN55,212-2 induced hypoactivity in the open field relative to vehicle-treated controls. By contrast, rimonabant, administered at a dose that virtually eliminated endocannabinoid-mediated stress antinociception, failed to alter locomotor behavior (i.e. time resting, ambulatory counts, distance traveled) in rats subjected to the same stressor. Rats exposed acutely to footshock were hypersensitive to the antinociceptive effects of WIN55,212-2 and Delta(9)-tetrahydrocannabinol (Delta(9)-THC). The converse was also true; acute Delta(9)-THC and WIN55,212-2 administration potentiated stress antinociception, suggesting a bidirectional sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception. Stress antinociception was also attenuated following chronic relative to acute treatment with WIN55,212-2 or Delta(9)-THC. Repeated exposure to footshock (3 min/day for 15 days), however, failed to attenuate antinociception induced by either footshock stress or WIN55,212-2. Our results demonstrate that endocannabinoid-mediated stress antinociception cannot be attributed to motor suppression. Our results further identify a functional plasticity of the cannabinoid system in response to repeated activation. The existence of cross-sensitization between endocannabinoid-mediated stress antinociception and exogenous cannabinoid antinociception suggests that these phenomena are mediated by a common mechanism. The observation of stress-induced hypersensitivity to effects of exogenous cannabinoids may have clinical implications for understanding marijuana abuse liability in humans.
authors: Neuroscience and Behavior Program, Department of Psychology, University of Georgia, Athens, GA 30602-3013, USA.
authors: Richard L
authors: RL
authors: Suplita
authors: Sarah A
authors: SA
authors: Eisenstein
authors: Mark H
authors: MH
authors: Neely
authors: Anna M
authors: AM
authors: Moise
authors: Andrea G
authors: AG
authors: Hohmann
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D048588:Benzoxazines / Q000627:therapeutic use*; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013759:Dronabinol / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D004361:Drug Tolerance / Q000502:physiology; D004597:Electroshock / Q000009:adverse effects; D063388:Endocannabinoids; D008297:Male; D009025:Morpholines / Q000627:therapeutic use*; D009043:Motor Activity / Q000187:drug effects; D009281:Naphthalenes / Q000627:therapeutic use*; D010147:Pain Measurement; D010880:Piperidines / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D000077285:Rimonabant; D013312:Stress, Physiological / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D013997:Time Factors
chemical_list: D000700:Analgesics; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D000077285:Rimonabant
references: Neuron. 2006 Aug 17;51(4):455-66
references: 16908411
references: Science. 2006 Jun 30;312(5782):1967-70
references: 16809545
references: Neuropharmacology. 2007 Feb;52(2):415-22
references: 17011598
references: Curr Opin Lipidol. 2007 Apr;18(2):129-40
references: 17353660
references: Prog Neuropsychopharmacol Biol Psychiatry. 2007 Apr 13;31(3):633-41
references: 17258369
references: Brain Res. 1986 Mar 12;368(1):101-6
references: 3955348
references: Eur J Neurosci. 2001 Sep;14(5):884-6
references: 11576193
references: Psychopharmacology (Berl). 2001 Nov;158(3):259-66
references: 11713615
references: Prostaglandins Leukot Essent Fatty Acids. 2002 Feb-Mar;66(2-3):269-85
references: 12052042
references: Nature. 2002 Aug 1;418(6897):530-4
references: 12152079
references: Pharmacol Biochem Behav. 2002 Nov;73(4):911-9
references: 12213538
references: J Adolesc. 2002 Dec;25(6):645-54
references: 12490182
references: Neuron. 2003 May 8;38(3):461-72
references: 12741992
references: Physiol Rev. 2003 Jul;83(3):1017-66
references: 12843414
references: Curr Opin Chem Biol. 2003 Aug;7(4):469-75
references: 12941421
references: Pharmacol Biochem Behav. 2003 Jul;75(4):809-21
references: 12957223
references: Nat Rev Neurosci. 2003 Nov;4(11):873-84
references: 14595399
references: Science. 1980 May 9;208(4444):623-5
references: 7367889
references: J Neurosci. 1981 Apr;1(4):358-63
references: 7264724
references: Pain. 1983 Jun;16(2):109-10
references: 6877845
references: J Pers Soc Psychol. 1986 Sep;51(3):564-77
references: 3489832
references: Pharmacol Biochem Behav. 1991 Nov;40(3):471-8
references: 1666911
references: Brain Res. 1993 Jul 9;616(1-2):293-302
references: 8395305
references: J Neurosci. 1996 Oct 15;16(20):6601-11
references: 8815936
references: Nature. 1998 Sep 24;395(6700):381-3
references: 9759727
references: Endocrinology. 2004 Dec;145(12):5431-8
references: 15331569
references: Neuropsychopharmacology. 2005 Mar;30(3):497-507
references: 15280883
references: Neuropsychopharmacology. 2005 Mar;30(3):508-15
references: 15525997
references: Neuropsychopharmacology. 2005 Mar;30(3):516-24
references: 15637635
references: Eur J Neurosci. 2005 Feb;21(4):1057-69
references: 15787710
references: J Pharmacol Exp Ther. 2005 Jul;314(1):329-37
references: 15831444
references: Pharmacol Biochem Behav. 2005 Jun;81(2):331-42
references: 15927244
references: Pharmacol Biochem Behav. 2005 Jun;81(2):387-95
references: 15935455
references: Nature. 2005 Jun 23;435(7045):1108-12
references: 15973410
references: Curr Opin Investig Drugs. 2005 Jul;6(7):672-9
references: 16044662
references: Neuropharmacology. 2005 Dec;49(8):1201-9
references: 16129456
references: Neuropharmacology. 2006 Mar;50(3):372-9
references: 16316669
references: Neurosci Lett. 2006 Apr 24;397(3):180-4
references: 16378681
references: Handb Exp Pharmacol. 2005;(168):367-83
references: 16596781
references: Handb Exp Pharmacol. 2005;(168):509-54
references: 16596786
references: Handb Exp Pharmacol. 2005;(168):691-717
references: 16596793
references: Trends Neurosci. 2006 Apr;29(4):225-32
references: 16483675
references: J Neurosci. 2006 Jun 21;26(25):6677-86
references: 16793875
references: Curr Med Chem. 2006;13(22):2669-80
references: 17017918