Effects of Buprenorphine Maintenance Dose on μ-Opioid Receptor Availability, Plasma Concentrations, and Antagonist Blockade in Heroin-Dependent Volunteers

Greenwald, Mark K.; Johanson, Chris E.; Moody, David E.; Woods, James H.; Kilbourn, Michael R.; Koeppe, Robert A.; Schuster, Charles R.; Zubieta, Jon Kar

doi:10.1038/sj.npp.1300251

Cited by 262 publications

(212 citation statements)

References 38 publications

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“…BP ND values for nonsmokers in our study are lower than findings reported in some previously published studies (38,39); however, these values were comparable to other studies (40,41). These differences in MOR BP ND may be attributable to the oversampling in our study of carriers of the OPRM1 G allele who have lower BP ND (comprising ∼50% of our sample versus 15-20% in the general population).…”

Section: Discussioncontrasting

confidence: 57%

Human Mu Opioid Receptor ( OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers

Ray

Ruparel²,

Newberg³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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131

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Evidence points to the endogenous opioid system, and the muopioid receptor (MOR) in particular, in mediating the rewarding effects of drugs of abuse, including nicotine. A single nucleotide polymorphism (SNP) in the human MOR gene (OPRM1 A118G) has been shown to alter receptor protein level in preclinical models and smoking behavior in humans. To clarify the underlying mechanisms for these associations, we conducted an in vivo investigation of the effects of OPRM1 A118G genotype on MOR binding potential (BP ND or receptor availability). Twenty-two smokers prescreened for genotype (12 A/A, 10 */G) completed two [ 11 C]carfentanil positron emission tomography (PET) imaging sessions following overnight abstinence and exposure to a nicotine-containing cigarette and a denicotinized cigarette. Independent of session, smokers homozygous for the wild-type OPRM1 A allele exhibited significantly higher levels of MOR BP ND than smokers carrying the G allele in bilateral amygdala, left thalamus, and left anterior cingulate cortex. Among G allele carriers, the extent of subjective reward difference (denicotinized versus nicotine cigarette) was associated significantly with MOR BP ND difference in right amygdala, caudate, anterior cingulate cortex, and thalamus. Future translational investigations can elucidate the role of MORs in nicotine addiction, which may lead to development of novel therapeutics.genetics | neuroimaging | tobacco W ith 1 billion tobacco users worldwide, nicotine dependence has a major impact on global health. Advances in medication development for nicotine dependence require an improved understanding of the neurobiology of this complex, relapsing brain disorder (1). Although multiple neurobiological mechanisms have been implicated, a growing body of evidence points to the endogenous opioid system, and the mu-opioid receptor (MOR) in particular, in mediating the reinforcing effects of drugs of abuse, including nicotine (2-5). Nicotine upregulates MOR mRNA and protein expression in brain regions important in drug reward in rodents (4, 6) and stimulates endogenous opioid release (7,8), resulting in MOR activation and dopamine release (9).Genetic variation in MORs can modulate the endogenous opioid system, thereby altering behavior. A common single nucleotide polymorphism (SNP) in the mu-opioid receptor gene (OPRM1 A118G) results in an amino acid exchange at a putative glycosylation site in the extracellular terminus of the MOR (10). This OPRM1 SNP has been associated with a variety of drug dependence phenotypes in rodent and human studies (11), including nicotine reward, nicotine withdrawal severity, and smoking relapse (12)(13)(14).Despite substantial attention to the OPRM1 A118G in drug addiction research, the precise function of this SNP has yet to be clarified. Although the minor (G) allele was originally thought to be a "gain-of-function" variant, on the basis of increased affinity of MOR agonists (15), other data suggest that the G allele is associated with reduced mRNA and protein expression (16,17)....

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Section: Discussioncontrasting

confidence: 57%

Human Mu Opioid Receptor ( OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers

Ray

Ruparel²,

Newberg³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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131

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“…It can be noted that significant differences were never found between the doses of buprenorphine used. This may be due to the finding of Greenwald et al (2003) that a dose of 16 mg results in 8072% mu opioid receptor occupancy, whereas twice this dose (32 mg) results in only 8472% occupation.…”

Section: Discussionmentioning

confidence: 84%

Rats Maintained Chronically on Buprenorphine Show Reduced Heroin and Cocaine Seeking in Tests of Extinction and Drug-Induced Reinstatement

Sorge

Rajabi

Stewart

2005

Neuropsychopharmacol

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Buprenorphine is being introduced as a maintenance therapy in opioid addiction, but it is not clear how buprenorphine will affect co-use of cocaine in opioid users. We examined the effects of chronic buprenorphine (BUP0: 0.0 mg/kg/day; BUP1.5: 1.5 mg/kg/day; BUP3: 3.0 mg/kg/day) on the locomotor activity effects of acute heroin (0.25 mg/kg, subcutaneously (s.c.)) and cocaine (20 mg/kg, intraperitoneally (i.p.)). Buprenorphine had no effect on the stimulatory effect of heroin, but potentiated the locomotor response to cocaine. To investigate further the interactions between buprenorphine (BUP1.5 and BUP3), heroin (0.125, 0.25 and 0.375 mg/kg, s.c.), and cocaine (10, 20 and 30 mg/kg, i.p.), we used in vivo microdialysis and high-performance liquid chromatography to analyze extracellular levels of dopamine (DA) in the nucleus accumbens (NAc). Buprenorphine attenuated the heroin-induced rise in NAc DA, but greatly potentiated the cocaine-induced rise. Finally, we examined the potential of the highest dose of buprenorphine (BUP3) to reduce heroin and cocaine seeking in the presence of drug-associated cues under extinction conditions and in tests for reinstatement induced by heroin (0.25 mg/kg, s.c.), cocaine (20 mg/kg, i.p.), and 15-min footshock stress (0.8 mA, 0.5 s/shock, 40 s mean OFF time) in rats trained to selfadminister both drugs. Buprenorphine reduced heroin and cocaine seeking during extinction and following acute heroin and cocaine priming injections, but had no effect on stress-induced reinstatement. These results indicate that the suppression of responding following priming injections of drugs did not result from reduced motor activity, but possibly from a reduction in the salience of drug-associated cues induced by chronic buprenorphine treatment.

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“…Since the rewarding effects of buprenorphine are likely to be mediated by d-and k-opioid receptors in addition to m-opioid receptors, buprenorphine might conceivably provide a prototype for clinical effectiveness through decreased m-opioid receptor availability (Greenwald et al, 2003;Zubieta et al, 2000). Such m-opioid receptor-selective partial agonists might even provide good adjuncts during detoxification.…”

Section: Effects Of Buprenorphine In Mor-ko Micementioning

confidence: 99%

Buprenorphine Antinociception is Abolished, but Naloxone-Sensitive Reward is Retained, in μ-Opioid Receptor Knockout Mice

Ide

Minami

Satoh

et al. 2004

Neuropsychopharmacol

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Buprenorphine is a relatively nonselective opioid receptor partial agonist that is used in the management of both pain and addiction. To improve understanding of the opioid receptor subtypes important for buprenorphine effects, we now report the results of our investigation on the roles of m-, d-, and k-opioid receptors in antinociceptive responses and place preferences induced by buprenorphine. Buprenorphine antinociception, assessed by hot-plate and tail-flick tests, was significantly reduced in heterozygous m-opioid receptor knockout (MOR-KO) mice and abolished in homozygous MOR-KO mice. In contrast, buprenorphine retained its ability to establish a conditioned place preference (CPP) in homozygous MOR-KO, although the magnitude of place preference was reduced as the number of copies of wild-type m-opioid receptor genes was reduced. The remaining CPP of buprenorphine was abolished by pretreatment with the nonselective opioid antagonist naloxone, but only partially blocked by pretreatment with either the d-selective opioid antagonist naltrindole or the k-selective opioid antagonist norbinaltorphimine. These data, and biochemical confirmation of buprenorphine actions as a partial d-, m-, and k-agonist, support the ideas that m-opioid receptors mediate most of analgesic properties of buprenorphine, but that m-and d-and/or k-opioid receptors are each involved in the rewarding effects of this drug.

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Effects of Buprenorphine Maintenance Dose on μ-Opioid Receptor Availability, Plasma Concentrations, and Antagonist Blockade in Heroin-Dependent Volunteers

Cited by 262 publications

References 38 publications

Human Mu Opioid Receptor ( OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers

Human Mu Opioid Receptor ( OPRM1 A118G) polymorphism is associated with brain mu-opioid receptor binding potential in smokers

Rats Maintained Chronically on Buprenorphine Show Reduced Heroin and Cocaine Seeking in Tests of Extinction and Drug-Induced Reinstatement

Buprenorphine Antinociception is Abolished, but Naloxone-Sensitive Reward is Retained, in μ-Opioid Receptor Knockout Mice

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