Opioid receptor and α 2 -adrenoceptor agonist binding sites in the postmortem brain of heroin addicts (original) (raw)
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Neuroscience Letters, 1997
To assess the status of opioid receptors in the human brain during the process of opiate addiction, the abundance of immunoreactive mopioid receptors was quantitated in postmortem brains of chronic opiate addicts who had died of a heroin or methadone overdose. The immunoreactive levels of the associated enzyme protein kinase C (PKC-a and z isoforms) and G proteins (Ga i1/2 subunits) were also assessed in the same brains. In the frontal cortex of opiate addicts, the abundance of m-opioid receptors was not different from that obtained in matched controls. The level of Ca 2 + -dependent PKC-a was decreased (25%), whereas that of the atypical PKC-z remained unchanged. The density of Ga i1/2 proteins also was found to be increased (40%). The results indicate that opiate addiction in humans does not appear to be associated with a reduced density of brain m-opioid receptors. The sustained down-regulation of PKC-a in the brain of opiate addicts would allow the up-regulation of Ga i1/2 proteins aimed at compensating the postulated desensitization of the m-opioid receptor system. © 1997 Elsevier Science Ireland Ltd.
Hypothalamus-pituitary-adrenal axis of heroin addicts
Drug and Alcohol Dependence, 1985
The hypothalamus-pituitary-adrenal axis of heroin addicts was investigated by evaluating plasma cortisol levels throughout the day in 37 heroin abusers (HA), 17 of whom showed detectable morphine levels, indicating heroin administration in the previous hours and in 12 controls. All HA showed lower cortisol levels in basal condition (100.7 f 61.7 ng/ ml, M * S.D.) compared to the control group (159.7 f 40.6,P< 0.05). Moreover all HA (65.1 f 28.9%), and in particular those taking heroin during the study (39.1 + 41.4%), show a reduced cortisol decrease in the evening, which was significantly lower than in controls (85.3 f 10.1%; P < 0.01).
The distribution of multiple opiate receptors in bovine brain
Brain Research, 1981
The distribution of # and 6 opiate receptors in bovine brain has been investigated using the selective radioligands [3H]morphine and D-[aH]AIa z, D-Leu'~-enkephalin. Their distributions were found to vary independently through different brain areas with up to a 10-fold difference between the ratio of bt to 6 binding sites for the substantia nigra and the dentate gyrus of the hippocampus.
European Journal of Pharmacology, 2008
Opioid and excitatory amino acid receptors contribute to morphine dependence, but there are no studies of their role in heroin dependence. Thus, mice injected with acute or chronic heroin doses in the present study were pretreated with one of the following selective antagonists: 7benzylidenenaltrexone (BNTX), naltriben (NTB), nor-binaltorphimine (nor-BNI; δ 1 , δ 2 , and κ opioid receptors, respectively), MK-801, or LY293558 (NMDA and AMPA excitatory amino acid receptors, respectively). Naloxone-precipitated withdrawal jumping frequency, shown here to be a reliable index of heroin dependence magnitude, was reduced by BNTX or NTB in mice injected with both acute and chronic heroin doses. In contrast, nor-BNI did not alter jumping frequencies in mice injected with an acute heroin dose but significantly increased them in mice receiving chronic heroin injections. Continuous MK-801 or LY293558 infusion, but not injection, reduced jumping frequencies during withdrawal from acute heroin treatment. Their delivery by injection was nonetheless effective against chronic heroin dependence, suggesting mechanisms not simply attributable to NMDA or AMPA blockade. These data indicate that whereas δ 1 , δ 2 , NMDA, and AMPA receptors enable acute and chronic heroin dependence, κ receptor activity limits the dependence liability of chronic heroin. With the exception of δ 1 receptors, the apparent role of these receptors to heroin dependence is consistent with their contribution to morphine dependence, indicating that there is substantial physiological commonality underlying dependence to both heroin and morphine. The ability of κ receptor blockade to differentially alter acute and chronic dependence supports previous assertions from studies with other opioids that acute an chronic opioid dependence are, at least in part, mechanistically distinct. Elucidating the substrates contributing to heroin dependence, and identifying their similarities and differences with those of other opioids such as morphine, may yield effective treatment strategies to the problem of heroin dependency.
Neuropharmacology, 2007
Lewis (LEW) and Fischer 344 (F344) rats show differential morphine self-administration rates. In this study, after animals of both strains self-administered morphine (1 mg/kg) or extinguished this behaviour for 3, 7 or 15 days, we measured the binding to, and functional state of m opioid receptors (MORs) as well as proenkephalin (PENK) mRNA content in several brain regions. The results showed that in most brain areas: 1) LEW rats had less binding to MORs in basal conditions than F344 rats; 2) after morphine self-administration, either one of the strains or both (depending on the brain area) showed increased levels of binding to MORs as compared to basal groups; and 3) these binding levels in morphine self-administration animals came down in each extinction group. Moreover, F344 rats exhibited, in general, an increased functionality of MORs after morphine self-administration, as compared to basal groups, which also went down during extinction. Finally, the basal content of PENK mRNA was lower in LEW rats than in F344 rats and it decreased more after self-administration; during extinction, the levels of PENK mRNA got normalized in this strain. This differential modulation of the endogenous opioid system might be related to the different rates of morphine self-administration behavior exhibited by both inbred rat strains.
Molecular Brain Research, 1998
The induction of c-fos mRNA in rat brain due to morphine treatment was analyzed by in situ hybridization. A single dose of up to 100 mgrkg given to naive rats elicited only a weak c-fos expression. However, rats that were repeatedly pretreated with morphine displayed a marked c-fos induction in a few brain areas in response to morphine application. These brain areas essentially comprised the dorsal striatum, the shell of the nucleus accumbens, and some cortical areas. The c-fos signal was transient and not due to a residual withdrawal. Naloxone-precipitated withdrawal led to a more intense c-fos expression which also encompassed a greater range of brain areas. A similar but weaker pattern was observed in case of spontaneous withdrawal. A low morphine dose suppressed the c-fos expression nearly completely and was not sufficient to elicit the morphine-like expression pattern of c-fos. The brain areas which responded strongly to withdrawal included the piriform cortex, septal and hypothalamic nuclei and parts of the thalamus. Taken together, our data indicate that in certain circumscribed brain areas including the dorsal striatum and the shell of the nucleus accumbens, a sensitization towards morphine takes place at the molecular level. These areas responded to morphine with an elevated c-fos expression only when morphine was repeatedly given previously. Sensitization processes are thought to be important for opiate dependence, in particular for the increased craving for the drug. Furthermore, our data indicate that in case of repeated application signs of withdrawal appear after each morphine dose at the molecular level. Repeated events of withdrawal were also implicated in the establishment of a drug dependence state. q 1998 Elsevier Science B.V. All rights reserved.