κ2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims

Julie K. Staley, Richard B. Rothman, Kenner C. Rice, John Partilla, Deborah C Mash

Research output: Contribution to journalArticle

71 Citations (Scopus)

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 β-[125iodo]-3,14-dihydroxy-17-cyclopropylmethyl-4,5 α- epoxymorphinan ([125I]IOXY) after pretreatment with the site-directed acylating agents 2-(p-ethoxybenzyl)-1-diethylaminoethyl-5- isothiocyanatobenzimidiazole-HCl (μ-selective) and N-phenyl-N-[1-(2-(4- isothiocyanato)-phenethyl)-4-piperidinyl]-propanamide-HCl (δ-selective) to examine the effect of cocaine exposure on the distribution and density of κ2 receptors in autopsy studies of human cocaine fatalities. The selective labeling of the κ2 receptor subtype was demonstrated by competition binding studies, which gave a pharmacological signature (IOXY ≤ (+)- bremazocine >> U50,488 ≤ U69,593) distinct from either the κ1 or κ3 receptor subtypes. Visualization of [125I[IOXY labeling revealed that κ2 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 κ2 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 κ2 receptors in the amygdala. These findings demonstrate for the first time that κ2 receptor numbers are upregulated by cocaine exposure. The molecular adaptation of κ2 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.

Original languageEnglish
Pages (from-to)8225-8233
Number of pages9
JournalJournal of Neuroscience
Volume17
Issue number21
StatePublished - Nov 6 1997

Fingerprint

Opioid Receptors
Cocaine
Brain
Dopamine
Nucleus Accumbens
Amygdala
Paranoid Disorders
Cocaine-Related Disorders
Entorhinal Cortex
Narcotic Antagonists
Drug and Narcotic Control
Gyrus Cinguli
Presynaptic Terminals
Prefrontal Cortex
Cerebral Cortex
Opioid Analgesics
Motivation
Autopsy
Emotions
Pharmacology

Keywords

  • κ opioid receptor
  • Cocaine
  • Delirium
  • Dopamine
  • Human brain
  • IOXY

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Staley, J. K., Rothman, R. B., Rice, K. C., Partilla, J., & Mash, D. C. (1997). κ2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims. Journal of Neuroscience, 17(21), 8225-8233.

κ2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims. / Staley, Julie K.; Rothman, Richard B.; Rice, Kenner C.; Partilla, John; Mash, Deborah C.

In: Journal of Neuroscience, Vol. 17, No. 21, 06.11.1997, p. 8225-8233.

Research output: Contribution to journalArticle

Staley, JK, Rothman, RB, Rice, KC, Partilla, J & Mash, DC 1997, 'κ2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims', Journal of Neuroscience, vol. 17, no. 21, pp. 8225-8233.
Staley, Julie K. ; Rothman, Richard B. ; Rice, Kenner C. ; Partilla, John ; Mash, Deborah C. / κ2 opioid receptors in limbic areas of the human brain are upregulated by cocaine in fatal overdose victims. In: Journal of Neuroscience. 1997 ; Vol. 17, No. 21. pp. 8225-8233.
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