ABSTRACT
An unbiased conditioned place preference paradigm and the microdialysis technique was used to evaluate the effect of (+)-morphine pretreatment on the conditioned place preference produced by (-)-morphine and the increased release of the dopamine produced by mu-opioid ligand endomorphin-1, respectively, in the posterior nucleus accumbens shell of the male CD rat. (-)-Morphine (2.5-10 microg) microinjected into the posterior nucleus accumbens shell dose-dependently produced the conditioned place preference. Pretreatment with (+)-morphine (0.1-10 pg) given into the posterior accumbens shell for 45 min dose-dependently attenuated the conditioned place preference produced by (-)-morphine (5 microg) given into the same posterior accumbens shell. However, higher doses of (+)-morphine (0.1 and 1 ng) were less effective in attenuating the (-)-morphine-produced conditioned place preference. Thus, like given systemically, (+)-morphine given into the posterior nucleus accumbens shell also induces a U-shaped dose-response curve for attenuating the (-)-morphine-produced conditioned place preference. Microinjection of mu-opioid agonist endomorphin-1 (1-10 microg) given into the ventral tegmental area dose-dependently increased the release of the extracellular dopamine in the posterior nucleus accumbens shell in the urethane-anesthetized rats. The increased dopamine caused by endomorphin-1 (10 microg) was completed blocked by the (+)-morphine (10 pg) pretreatment given into ventral tegmental area. It is concluded that (+)-morphine attenuates the (-)-morphine-produced conditioned place preference and the mu-opioid receptor-mediated increase of extracellular dopamine in the posterior nucleus accumbens shell of the rat.
Subject(s)
Analgesics, Opioid/antagonists & inhibitors , Analgesics, Opioid/pharmacology , Conditioning, Operant/drug effects , Dopamine/metabolism , Morphine/antagonists & inhibitors , Morphine/pharmacology , Nucleus Accumbens/metabolism , Receptors, Opioid, mu/drug effects , Analgesics, Opioid/chemistry , Anesthesia , Animals , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Electrochemistry , Male , Microinjections , Morphine/chemistry , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Nucleus Accumbens/anatomy & histology , Nucleus Accumbens/drug effects , Oligopeptides/administration & dosage , Oligopeptides/pharmacology , Rats , Stereoisomerism , Ventral Tegmental AreaABSTRACT
An unbiased conditioned place preference paradigm was used to evaluate the effect of dextro-morphine on the morphine-produced reward in male CD rats. Morphine sulfate (1-10 mg/kg) given intraperitoneally dose-dependently produced the conditioned place preference. Pretreatment with dextro-morphine at a dose from 0.1 to 3 microg/kg given subcutaneously dose-dependently attenuated the morphine-produced conditioned place preference. However, dextro-morphine at a higher dose 100 microg/kg did not affect the morphine-produced conditioned place preference. Thus, dextro-morphine pretreatment induces a U-shaped dose-response curve for attenuating the morphine-produced conditioned place preference. The attenuation of the morphine-produced conditioned place preference was reversed by the pretreatment with the sigma(1) receptor antagonist BD1047 (N-[2-(3,4-Dichlorophenyl)ethyl]-N-methyl-2-(dimethylamino)ethylamine dihydrobromide. dextro-Morphine or BD1047 given alone did not affect the baseline place conditioning. It is concluded that dextro-morphine attenuated the morphine-produced conditioned place preference via the sigma(1) receptor activation.
Subject(s)
Analgesics, Opioid/pharmacology , Conditioning, Operant/drug effects , Morphine/pharmacology , Receptors, sigma/drug effects , Analysis of Variance , Animals , Dose-Response Relationship, Drug , Ethylenediamines , Injections, Intraperitoneal , Injections, Subcutaneous , Male , Rats , Receptors, sigma/metabolism , Reward , Stereoisomerism , Sigma-1 ReceptorABSTRACT
It is generally accepted that neuropathic pain is resistant to amelioration by morphine in clinical studies and insensitivity to intrathecal (i.t.) administered morphine in experimental models of neuropathic pain has been demonstrated. This study is to determine if endogenous dynorphin, substance P or cholecystokinin is involved in the lack of anti-allodynia of morphine in a partial sciatic nerve ligation (PSL) model of CD-1 mice. Mice exhibited tactile allodynia in the ipsilateral hind paw 1 day after PSL, and reached its maximal allodynic effect at 2 days and remained allodynic for 7 days. Morphine (3.0 nmol) given i.t. did not alter the tactile allodynic threshold in ipsilateral paw of mice pretreated i.t. with normal rabbit serum 2 days after PSL. However, the same dose of morphine (3.0 nmol) given i.t. reduced markedly allodynia in mice pretreated for 2h with antiserum against dynorphin A(1-17) (200 microg); the morphine-produced anti-allodynia developed slowly, reached its peak effect at 30 min and returned to an allodynic state in 60 min. Similarly, i.t. injection of morphine reduced the allodynia in PSL mice pretreated with antiserum against substance P (10 microg) or cholecystokinin (200 microg) for 2h. Intrathecal pretreatment with antiserum against dynorphin A(1-17), substance P or cholecystokinin for 2h injected alone did not affect the baseline mechanical tactile threshold in ipsilateral paw 2 days after PSL. The results indicate that endogenous dynorphin A(1-17), substance P and cholecystokinin are involved in PSL-induced neuropathic allodynia to attenuate the anti-allodynic effect of morphine.
Subject(s)
Cholecystokinin/antagonists & inhibitors , Dynorphins/antagonists & inhibitors , Immune Sera/pharmacology , Morphine/agonists , Neuralgia/drug therapy , Peripheral Nervous System Diseases/drug therapy , Substance P/antagonists & inhibitors , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/agonists , Animals , Antibodies/pharmacology , Antibodies/therapeutic use , Cholecystokinin/metabolism , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Resistance/drug effects , Drug Resistance/physiology , Drug Synergism , Dynorphins/metabolism , Injections, Spinal , Ligation , Male , Mice , Morphine/administration & dosage , Neuralgia/metabolism , Neuralgia/physiopathology , Peripheral Nervous System Diseases/metabolism , Peripheral Nervous System Diseases/physiopathology , Sciatic Nerve/injuries , Sciatic Nerve/surgery , Sciatic Neuropathy/drug therapy , Sciatic Neuropathy/metabolism , Sciatic Neuropathy/physiopathology , Substance P/metabolismABSTRACT
An unbiased conditioned place preference (CPP) paradigm was used to evaluate the reward effects of endogenous mu-opioid receptor ligands endomorphin-1 (EM-1) and endomorphin-2 (EM-2) from the mesolimbic posterior nucleus accumbens (Acb) shell and the ventral tegmental area (VTA) in CD rats. EM-1 (1.6-8.1 nmol) microinjected into posterior Acb shell produced CPP, whereas EM-2 (8.7-17.5 nmol) given into the same Acb shell produced conditioned place aversion (CPA). EM-1 (1.6-16.3 nmol) microinjected into the VTA produced CPP, whereas EM-2 (8.7 and 17.5 nmol) given into the same VTA site did not produce any effect, but at a high dose (35 nmol) produced CPP. EM-1 (3.3 nmol) or EM-2 (17.5 nmol) microinjected into the nigrostriatal substantia nigra was not significantly different from vehicle-injected groups. D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) at 94.13 pmol or 3-methoxynaltrexone at 0.64 pmol microinjected into the posterior Acb shell blocked EM-1-induced CPP and EM-2-induced CPA. At a higher dose, CTOP (941.3 pmol) and 3-methoxynaltrexone (6.4 pmol) produced CPA and CPP, respectively. Coadministration with antiserum against dynorphin A(1-17) (Dyn) (10 microg) microinjected into the posterior Acb shell blocked EM-2-induced CPA. However, it did not affect EM-1-induced CPP. It is concluded that EM-1 and EM-2 produce site-dependent CPP and CPA, respectively, by stimulation of different subtypes of mu-opioid-receptors; stimulation of one subtype of mu-opioid-receptor at the posterior Acb shell and VTA by EM-1 induces CPP, whereas stimulation of another subtype of mu-opioid receptor at the posterior Acb shell, but not the VTA, by EM-2 induces the release of Dyn to produce CPA.
