Orexin Mediates the Expression of Precipitated Morphine Withdrawal and Concurrent Activation of the Nucleus Accumbens Shell

Sharf, Ruth; Sarhan, Maysa; DiLeone, Ralph J.

doi:10.1016/j.biopsych.2008.03.006

Cited by 131 publications

(94 citation statements)

References 58 publications

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“…or reported maximum effects at high doses (20-30 mg/kg i.p. ; Boutrel et al 2005;Harris et al 2005;Lawrence et al 2006;Richards et al 2008;Sakurai et al 1998;Sharf et al 2008). Brain levels of SB-334867 reach about 14 μM at only 10 mg/kg i.p., which should be more than enough for full effects in vivo, given its Ki of about 60 nM (Upton 2005).…”

Section: Discussionmentioning

confidence: 97%

“…It has been shown that the orexin-1 receptor antagonist SB-334867 attenuates morphine-conditioned place preference (CPP) and reinstatement (Harris et al 2005(Harris et al , 2007Narita et al 2006), stressinduced cocaine reinstatement (Boutrel et al 2005); but see lack of effect of intra-VTA orexin-1 receptor blockade on stress-induced cocaine reinstatement (Wang et al 2009), cueinduced cocaine reinstatement ), cocaineinduced synaptic plasticity and sensitization (Borgland et al 2006), and intake and cue-and stress-induced reinstatement of ethanol (Lawrence et al 2006;Richards et al 2008;Sakurai et al 1998). In addition, SB-334867 attenuates precipitated morphine withdrawal (Sharf et al 2008) and nicotine self-administration (Hollander et al 2008). …”

Section: Introductionmentioning

confidence: 98%

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Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

et al. 2010

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 98%

Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

et al. 2010

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“…The OX 1 receptor seems to mediate both the reinforcing and incentive motivational properties of opiates as systemic SB-334867 administration reduces operant selfadministration, progressive ratio breakpoint and cueinduced (but not drug-primed) reinstatement of heroinseeking [108]. SB-334867 also reduces morphine withdrawal in mice, suggesting OX 1 receptor involvement in this phenomenon [109]. No definitive role for the OX 2 receptor, however, has been established in opiate-seeking as yet.…”

Section: Orexin and Opiatesmentioning

confidence: 96%

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Khoo

Brown

2014

CNS Drugs

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Addiction is a chronic relapsing disorder which presents a significant global health burden and unmet medical need. The orexin/hypocretin system is an attractive potential therapeutic target as demonstrated by the successful clinical trials of antagonist medications like Suvorexant for insomnia. It is composed of two neuropeptides, orexin-A and orexin-B and two excitatory and promiscuous G-protein coupled receptors, OX1 and OX2. Orexins are known to have a variety of functions, most notably in regulating arousal, appetite and reward. The orexins have been shown to have a role in mediating the effects of several drugs of abuse, such as cocaine, morphine and alcohol via projections to key brain regions such as the ventral tegmental area, nucleus accumbens and prefrontal cortex. However, it has not yet been demonstrated whether the dual orexin receptor antagonists (DORAs) under development for insomnia are ideal drugs for the treatment of addiction. The question of whether to use a DORA or single orexin receptor antagonist (SORA) for the treatment of addiction is a key question that will need to be answered in order to maximize the clinical utility of orexin receptor antagonists. This review will examine the role of the orexin/hypocretin system in addiction, orexin-based pharmacotherapies under development and factors affecting the selection of one or both orexin receptors as drug targets for the treatment of addiction.

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“…It has been shown that chronic opioid administration in rodents promoted GABA-mediated excitation [14] and loss of neuronal inhibition via reduction of KCC 2 currents in the ventral tegmental area [15]. Furthermore, acute morphine withdrawal in rats increased c-Fos expression in dopaminergic neurons within nucleus accumbens shell in mice [16], and phosphorylation of NMDARs in the accumbens [17]. These studies imply that neuronal hyperexcitability within the limbic regions may alter activity within the dopamine-dependent motivation system, thus producing aversive effects to opioid withdrawal and reinforcing future drug seeking behaviors.…”

Section: Central Mechanisms Of Opioid Withdrawalmentioning

confidence: 99%

Therapies and Mechanisms of Opioid Withdrawal

2017

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Opioids are revered as potent analgesics, yet their clinical utility for managing pain is shrouded by concerns over the high abuse potential. With skyrocketing numbers of opioid prescriptions and off-label use, and a striking number of accidental opioid-related deaths and emergency room visits, North America has declared an 'opioid crisis'. In the USA alone, the number of prescribed opioids has quadrupled since 1999, with enough opioid prescriptions dispensed annually to provide a bottle for every household [1]. The opioid crisis, however, is not an isolated North American problem as virtually all developed countries have reported increased opioid consumption and deaths. The alarming rise in opioid-related deaths has stoked growing concerns about the safety of opioids, and increased reluctance on the part of some physicians to prescribe this class of drugs. This has created a conundrum: on one hand, opioids are essential for managing pain, but an over-reliance on opioids can put patients at risk of serious adverse effects, such as opioid analgesic tolerance (diminished pain-relieving effects), hyperalgesia (paradoxical increase in pain sensitivity) and drug dependence (manifesting as drug craving, seeking and/or physical withdrawal). The problem of opioid withdrawalAlthough adverse effects undermine the long-term clinical utility of opioids for pain management, terminating opioid therapy is also problematic because it can precipitate a debilitating withdrawal syndrome in chronic users. In this respect, opioid withdrawal is a significant challenge in patients where pain has resolved and there is no longer a need for opioid treatment, or those that are on dangerously high doses and a reduction in dose is prudent. Depending on the half-life of the opioid used, withdrawal typically presents between 8 and 48 h after the last opioid dose, with symptoms including gastrointestinal discomfort, anxiety, insomnia, muscle cramps and hyperhidrosis [2]. Individuals are therefore compelled to continue using opioids to avoid these unpleasant somatic, autonomic and emotional symptoms. Thus opioid withdrawal is a key determinant for continued opioid use and a contributing factor for relapse. A potential complication of terminating opioid therapy is the re-emergence of pain or exacerbation of a preexisting pain condition. Although pain is a major concern, patients on opioid therapy report that mitigation of withdrawal is a more important consideration for continued opioid use than pain management [3]. However, discerning between pain from a pre-existing condition and pain arising from opioid withdrawal is difficult. Patients may demand higher doses of opioids to manage a perceived worsening of pain, but the underlying reason may stem from withdrawal rather than a progression of a pre-existing pain condition. Withdrawal is also a key motivating factor for continued opioid use in off-label or nonprescription opioid users, and like prescription opioid users, many of these individuals may be better positioned to stop opioid use if mor...

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Orexin Mediates the Expression of Precipitated Morphine Withdrawal and Concurrent Activation of the Nucleus Accumbens Shell

Cited by 131 publications

References 58 publications

Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

Selective blockade of the orexin-2 receptor attenuates ethanol self-administration, place preference, and reinstatement

Orexin/Hypocretin Based Pharmacotherapies for the Treatment of Addiction: DORA or SORA?

Therapies and Mechanisms of Opioid Withdrawal

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