Nicotine and endogenous opioids: Neurochemical and pharmacological evidence

Abstract

Although the mesolimbic dopamine hypothesis is the most influential theory of nicotine reward and reinforcement, there has been a consensus that other neurotransmitter systems contribute to the addictive properties of nicotine as well. In this regard, the brain opioidergic system is of interest. Striatum is rich in opioid peptides and opioid receptors, and striatal opioidergic neurons are engaged in a bidirectional communication with midbrain dopaminergic neurons, closely regulating each other’s activity. Enkephalins and dynorphins exert opposing actions on dopaminergic neurons, increasing and decreasing dopamine release respectively, and are components of circuits promoting positive or negative motivational and affective states. Moreover, dopamine controls the synthesis of striatal enkephalins and dynorphins. Evidence suggests that opioidergic function is altered after nicotine and endogenous opioids are involved in nicotine’s behavioral effects. 1) The synthesis and release of β-endorphin, met-enkephalin and dynorphin in brain, especially nucleus accumbens (NAc), are altered after acute or chronic nicotine treatment and during nicotine withdrawal. 2) Although opioid receptor binding and mRNA do not appear to change in the striatum during nicotine withdrawal, the activity of κ-opioid (KOPr) and δ-opioid (DOPr) receptors is attenuated in NAc. 3) The nicotine withdrawal syndrome reminisces that of opiates, and naloxone precipitates some of its somatic, motivational, and affective signs. 4) Genetic and pharmacological studies indicate that μ-opioid (MOPr) receptors are mainly involved in nicotine reward, while DOPrs contribute to the emotional and KOPrs to the aversive responses of nicotine. 5) Finally, MOPrs and enkephalin, but not β-endorphin or dynorphin, are necessary for the physical manifestations of nicotine withdrawal.

This article is part of a Special Issue entitled ‘Trends in Neuropharmacology: In Memory of Erminio Costa’.

Introduction

In 1985, when the Laboratory of Preclinical Pharmacology (LPP), NIMH, closed at St. Elizabeths Hospital, Washington, DC, Erminio Costa (Mimo) summarized ten research advances that he felt had been achieved during the life of LPP (1968–1985). Among them two were related to the opioid peptides: 1) “First proposed that opioid peptides function as neuromodulators in structures that are not involved in pain threshold regulation, such as caudate nucleus, adrenal medulla and sympathetic ganglia” and 2) “Elucidated endogenous mechanisms operative in opiate tolerance” (Costa, 1985). Over the 17 year span of LPP’s existence more than 100 publications dealing with different aspects of opioids including location, metabolism, receptors and pharmacology originated from LPP (Costa, 1985). Since then, the endogenous opioid system has evolved as an important neurosubstrate for the addictive properties of drugs of abuse, including nicotine. This paper is a review of the existing literature on nicotine and endogenous opioids along with a presentation of our work that was motivated by our association with Mimo. A discussion of the role of dopamine in nicotine psychopharmacology and the interactions between dopamine and endogenous opioids has been included as background information. We write this review in tribute to Mimo for his visionary dedication to neuroscience research, and the tireless training he provided to hundreds of scientists from around the globe, including us.