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PMID: 9334398 Published · ppublish English Comparative Study Journal Article Research Support, U.S. Gov't, P.H.S.

Kappa2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 17 ·No. 21 ·1997-11-01 ·Pages 8225-33

Staley JK, Rothman RB, Rice KC, Partilla J, Mash DC

Abstract

Cocaine is thought to be addictive because chronic use leads to molecular adaptations within the mesolimbic dopamine (DA) circuitry that affect motivated behavior and emotion. Although the reinforcing effects of cocaine are mediated primarily by blocking DA reuptake into the presynaptic nerve terminal, reciprocal signaling between DA and endogenous opioids has important implications for cocaine dependence. The present study used the opioid antagonist 6 beta-[125iodo]-3,14-dihydroxy-17-cyclopropylmethyl-4,5 alpha-epoxymorphinan ([125I]IOXY) after pretreatment with the site-directed acylating agents 2-(p-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimid iazole -HCl (mu-selective) and N-phenyl-N-[1-(2-(4-isothiocyanato)-phenethyl)-4-piperidinyl]-p ropana mide-HCl (delta-selective) to examine the effect of cocaine exposure on the distribution and density of kappa2 receptors in autopsy studies of human cocaine fatalities. The selective labeling of the kappa2 receptor subtype was demonstrated by competition binding studies, which gave a pharmacological signature (IOXY >/= (+)-bremazocine >> U50,488 >/= U69,593) distinct from either the kappa1 or kappa3 receptor subtypes. Visualization of [125I]IOXY labeling revealed that kappa2 receptors localize to mesocortical and subcortical limbic areas, including the cingulate, entorhinal, insular, and orbitofrontal cortices and the nucleus accumbens and amygdala. The number of kappa2 receptors in the nucleus accumbens and other limbic brain regions from cocaine fatalities was increased twofold as compared with age-matched and drug-free control subjects. Cocaine overdose victims, who experienced paranoia and marked agitation before death, also had elevated densities of kappa2 receptors in the amygdala. These findings demonstrate for the first time that kappa2 receptor numbers are upregulated by cocaine exposure. The molecular adaptation of kappa2 receptor numbers may play a role in the motivational incentive associated with episodes of binge cocaine use and in the dysphoria that follows abrupt cocaine withdrawal.

MeSH Terms
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/metabolism Adult Amygdala/chemistry Benzeneacetamides Benzomorphans/metabolism Binding, Competitive Brain/pathology Brain Chemistry/drug effects Caudate Nucleus/chemistry Cocaine/adverse effects,analysis,pharmacokinetics,pharmacology Dopamine/metabolism Dopamine Uptake Inhibitors/pharmacology,poisoning Drug Overdose Female Fentanyl/analogs & derivatives,metabolism Gyrus Cinguli/chemistry Humans Isothiocyanates/metabolism Kinetics Male Morphinans/metabolism,pharmacokinetics Protein Binding Pyrrolidines/metabolism Receptors, Opioid, kappa/drug effects,genetics,metabolism Tissue Distribution Up-Regulation/drug effects
Chemicals
Benzeneacetamides Benzomorphans Dopamine Uptake Inhibitors Isothiocyanates Morphinans Pyrrolidines Receptors, Opioid, kappa kappa(2) opioid receptor 6-iodo-3,14-dihydroxy-17-(cyclopropylmethyl)-4,5-epoxymorphinan 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer fentanyl isothiocyanate 2-(4-ethoxybenzyl)-1-diethylaminoethyl-5-isothiocyanatobenzimidazole Cocaine bremazocine U 69593 Fentanyl Dopamine
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Staley J K
Department of Neurology and Molecular and Cellular Pharmacology and The Comprehensive Drug Research Center, University of Miami School of Medicine, Miami, Florida 33101, USA.
Rothman R B
Rice K C
Partilla J
Mash D C
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
0270-6474
Published
1997-11-01
Pages
8225-33
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6573759
Subset
IM
Grants
NIDA NIH HHS · DA-06227 · United States
External Links
PubMed source PMC Full Text View journal details
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