Opioid Withdrawal Syndrome: Emerging Concepts and Novel Therapeutic Targets

Abstract

Opioid withdrawal syndrome is a debilitating manifestation of opioid dependence and responds poorly to the available clinical therapies. Studies from various in vivo and in vitro animal models of opioid withdrawal syndrome have led to understanding of its pathobiology which includes complex interrelated pathways leading to adenylyl cyclase superactivation based central excitation. Advancements in the elucidation of opioid withdrawal syndrome mechanisms have revealed a number of key targets that have been hypothesized to modulate clinical status. The present review discusses the neurobiology of opioid withdrawal syndrome and its therapeutic target recptors like calcitonin gene related peptide receptors (CGRP), N-methyl-D-aspartate (NMDA) receptors, gamma aminobutyric acid receptors (GABA), G-proteingated inwardly rectifying potassium (GIRK) channels and calcium channels. The present review further details the potential role of second messengers like calcium (Ca2+) / calmodulin-dependent protein kinase (CaMKII), nitric oxide synthase, cytokines, arachidonic acid metabolites, corticotropin releasing factor, fos and src kinases in causing opioid withdrawal syndrome. The exploitation of these targets may provide effective therapeutic agents for the management of opioid dependence-induced abstinence syndrome.

Endothelin ETAreceptor antagonist reverses naloxone-precipitated opioid withdrawal in mice

“…Jumping, rearing, and wet shakes are reliable indicators of precipitated withdrawal in animal models (Gomaa et al 1989;Martin and Takemori 1987;Ramesh et al 2011;Rehni et al 2013;Way et al 1969). Clinically, these behaviors correlate with withdrawal symptoms such as tremors, shakes, and jitters (Gold et al 1978;Kosten and George 2002;Krantz and Mehler 2004;Kreek and Koob 1998).…”

“…The effectiveness of these drugs can be limited by the development of tolerance, dependence and subsequent withdrawal. Some of the adverse effects of opioid withdrawal include sedation, respiratory depression, cramps, changes in body temperature, diarrhea and emesis (Doyon 2004;Krantz and Mehler 2004;Rehni et al 2013;Schug et al 1992). A large number of patients undergoing opioid withdrawal also exhibit debilitating withdrawal symptoms such as tachycardia, cardiac arrhythmias, hypertension, anxiety, stroke and seizures (Himmelsbach 1937;Jackson et al 2013;Martin and Jasinski 1969).…”

“…Studies in rodents suggest that central α-adrenergic receptors are involved in opioid withdrawal (Cedarbaum and Aghajanian 1977;Gomes et al 1976; Lewis et al 1976;Redmond 1977;Rehni et al 2013;Svensson et al 1975;Tseng et al 1975). Opioid withdrawal symptoms are due to increased noradrenergic neuronal activity in areas such as the locus coeruleus (Kosten and George 2002;Moore and Bloom 1979;Williams et al 2001) which are regulated both by α 2 adrenergic and opioid receptors.…”

“…Opioid withdrawal symptoms are due to increased noradrenergic neuronal activity in areas such as the locus coeruleus (Kosten and George 2002;Moore and Bloom 1979;Williams et al 2001) which are regulated both by α 2 adrenergic and opioid receptors. Clonidine, an α 2 adrenergic receptor agonist, is used for relieving withdrawal symptoms due to its sympatholytic activity (Gold et al 1978;Krantz and Mehler 2004;Rehni et al 2013). Since ET A receptor antagonists also have sympatholytic activity, we hypothesize that ET A receptors are involved in opioid withdrawal.…”

Neonatal Abstinence Syndrome

“…Ultimately, this results in the increased production of various neurotransmitters through a cascade of enzymatic activities (Fig 2). 77 The most important center of activity in opioid withdrawal is the locus coeruleus of the pons. This is the principal noradrenergic nucleus of the brain and is extremely sensitive to opioid status.…”