Brain Region-Specific Mechanisms for Acute Morphine-Induced Mitogen-Activated Protein Kinase Modulation and Distinct Patterns of Activation during Analgesic Tolerance and Locomotor Sensitization

The mechanisms underlying responses to drugs of abuse have been widely investigated; however, less is known about pathways normally protective against the development of drug reinforcement. These pathways are also important since they may regulate individual differences in vulnerability to addiction. The neuropeptide galanin and its binding sites are expressed in brain areas important for drug reward. Previous studies have shown that centrally infused galanin attenuates morphine place preference and peripheral injection of galnon, a galanin agonist, decreases opiate withdrawal signs. The current studies in galanin knockout (GKO) mice examined the hypothesis that galanin is an endogenous negative regulator of opiate reward and identified downstream signaling pathways regulated by galanin. We show that GKO mice demonstrate increased locomotor activation following morphine administration, which is inhibited by acute administration of galnon. GKO mice also show enhanced morphine place preference, supporting the idea that galanin normally antagonizes opiate reward. In addition, morphine-induced ERK1/2 phosphorylation was increased in the VTA of both wild-type and GKO mice, but only the GKO mice showed increases in ERK1/2 and CREB phosphorylation in the amygdala or nucleus accumbens. Furthermore, a single systemic injection of galnon in GKO mice was sufficient to reverse some of the biochemical changes brought about by morphine administration. These data suggest that galanin normally attenuates behavioral and neurochemical effects of opiates; thus, galanin agonists may represent a new class of therapeutic targets for opiate addiction.

Section: Discussionsupporting

confidence: 80%

Galanin Protects Against Behavioral and Neurochemical Correlates of Opiate Reward

Hawes

Brunzell

Narasimhaiah

et al. 2007

“…The subthalamic nucleus is regulated by m-opioid agonists (Shen and Johnson, 2002), but it is not known if these become sensitized with repeated activation. However, the basolateral amydgala demonstrates enhancements in receptor-mediated signaling cascades (ie MAPK) in morphine-sensitized rats (Eitan et al, 2003). Thus, it is possible that a sensitized glutamatergic drive to the VP is associated with morphine-induced behavioral sensitization.…”

Section: Discussionmentioning

confidence: 99%

The Ventral Pallidum is Critically Involved in the Development and Expression of Morphine-Induced Sensitization

Mickiewicz

Dallimore

Napier

2008

Repeated, intermittent exposure to drugs of abuse results in response enhancements to subsequent drug treatments, a phenomenon referred to as sensitization. As persistent neuronal sensitization may contribute to the long-lasting consequences of drug abuse, characterizing the neuroanatomical substrates of sensitization is providing insights into addiction. It is known that the ventral tegmental area (VTA) is necessary for induction, and expression involves the nucleus accumbens (NAc). We reveal here that the ventral pallidum (VP), a brain region reciprocally innervated by the VTA and the NAc, is a critical mediator of opiate-induced behavioral sensitization. Blockade of VP m-opioid receptors (via intra-VP CTOP injections) negated the ability of systemic administration of the opiate, morphine to induce motor sensitization, and for sensitized rats to subsequently express enhanced responding to a morphine challenge. Intra-VP morphine was sufficient to induce motor sensitization, and this sensitization was expressed following 17 days of withdrawal. Rats with a treatment history of intra-VP morphine demonstrated cross-sensitization to a challenge injection of systemically administered morphine. Conversely, repeated systemic treatments of morphine cross-sensitized to an intra-VP morphine challenge. These results indicate that activation of VP m-opioid receptors is sufficient to evoke behavioral sensitization and that these receptors are necessary for sensitized responding to systemic morphine. The study pioneers the concept that both development and expression of drug-induced sensitization are regulated by the VP. Thus, the VP is likely an important contributor to neuronal adaptations that underlie addiction.

“…Repeated opiate use decreases dendritic spine density on pyramidal cells in the mPFC (Robinson and Kolb, 1999), a form of reorganization of structural plasticity that is possibly mediated by molecules regulating neuronal and synaptic structure (Lamprecht and LeDoux, 2004). In the amygdala, acute opiate administration decreases levels of Chronic morphine and fear extinction C Gu et al activated mitogen-activated protein kinases (Eitan et al, 2003), which have been implicated in synaptic plasticity (Sweatt, 2004). Opiate withdrawal increases levels of phosphorylated cAMP response element binding (CREB) protein in the amygdala (Shaw-Lutchman et al, 2002), and CREB may be critical for withdrawal-dependent synaptic plasticity (Nestler, 2001).…”

Section: Discussionmentioning

confidence: 99%

Chronic Morphine Selectively Impairs Cued Fear Extinction in Rats: Implications for Anxiety Disorders Associated with Opiate Use

et al. 2007

Previous studies have shown that opioid transmission plays an important role in learning and memory. However, little is known about the course of opiate-associated learning and memory deficits after cessation of chronic opiate use in a behavioral animal model. In the present study, we examined the effects of chronic morphine on fear extinction, an important preclinical model for behavior therapy of human anxiety disorders. Rats were administrated subcutaneously morphine hydrochloride or saline twice per day for continuous 10 days. Rats received a cued or contextual fear conditioning session 7 days after the last morphine injection. During subsequent days, rats received four cued or contextual extinction sessions (one session per day). Percent freezing was assessed during all phases of training. Chronic morphine did not affect the acquisition of cued fear response or the initial encoding of extinction memory within each session, but produced an impairment in the between-session extinction. However, the same morphine treatment schedule did not affect the acquisition or extinction of contextual fear response. These results suggest that the effects of chronic morphine on memory for fear extinction are complex. Chronic morphine selectively impairs extinction of cued fear response. This deficit in fear extinction may be one of those critical components that contribute to the high prevalence of anxiety disorders in opiate addicts.