Role in treatment of drug addiction
KOR agonists have recently been investigated for their therapeutic potential in the treatment of addiction[43] and evidence points towards dynorphin, the endogenous KOR agonist, to be the body's natural addiction control mechanism.[44] Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the MOR and KOR systems.[45] In experimental "addiction" models the KOR has also been shown to influence stress-induced relapse to drug seeking behavior. For the drug dependent individual, risk of relapse is a major obstacle to becoming drug free. Recent reports demonstrated that KORs are required for stress-induced reinstatement of cocaine seeking.[46][47]
One area of the brain most strongly associated with addiction is the nucleus accumbens (NAcc) and striatum while other structures that project to and from the NAcc also play a critical role. Though many other changes occur, addiction is often characterized by the reduction of dopamine D2 receptors in the NAcc.[48] In addition to low NAcc D2 binding,[49][50] cocaine is also known to produce a variety of changes to the primate brain such as increases prodynorphin mRNA in caudate putamen (striatum) and decreases of the same in the hypothalamus while the administration of a KOR agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.[51]
Additionally, while cocaine overdose victims showed a large increase in KORs (doubled) in the NAcc,[52] KOR agonist administration is shown to be effective in decreasing cocaine seeking and self-administration.[53] Furthermore, while cocaine abuse is associated with lowered prolactin response,[54] KOR activation causes a release in prolactin,[55] a hormone known for its important role in learning, neuronal plasticity and myelination.[56]
It has also been reported that the KOR system is critical for stress-induced drug-seeking. In animal models, stress has been demonstrated to potentiate cocaine reward behavior in a kappa opioid-dependent manner.[57][58] These effects are likely caused by stress-induced drug craving that requires activation of the KOR system. Although seemingly paradoxical, it is well known that drug taking results in a change from homeostasis to allostasis. It has been suggested that withdrawal-induced dysphoria or stress-induced dysphoria may act as a driving force by which the individual seeks alleviation via drug taking.[59] The rewarding properties of drug are altered, and it is clear KOR activation following stress modulates the valence of drug to increase its rewarding properties and cause potentiation of reward behavior, or reinstatement to drug seeking. The stress-induced activation of KORs is likely due to multiple signaling mechanisms. The effects of KOR agonism on dopamine systems are well documented, and recent work also implicates the mitogen-activated protein kinase cascade and pCREB in KOR-dependent behaviors.[24][60]
Though cocaine abuse is a frequently used model of addiction, KOR agonists have very marked effects on all types of addiction including alcohol, cocaine and opiate abuse.[10] Not only are genetic differences in dynorphin receptor expression a marker for alcohol dependence but a single dose of a KOR antagonist markedly increased alcohol consumption in lab animals.[61] There are numerous studies that reflect a reduction in self-administration of alcohol,[62] and heroin dependence has also been shown to be effectively treated with KOR agonism by reducing the immediate rewarding effects[63] and by causing the curative effect of up-regulation (increased production) of MORs[64] that have been down-regulated during opioid abuse.
The anti-rewarding properties of KOR agonists are mediated through both long-term and short-term effects. The immediate effect of KOR agonism leads to reduction of dopamine release in the NAcc during self administration of cocaine[65] and over the long term up-regulates receptors that have been down-regulated during substance abuse such as the MOR and the D2 receptor. These receptors modulate the release of other neurochemicals such as serotonin in the case of MOR agonists and acetylcholine in the case of D2. These changes can account for the physical and psychological remission of the pathology of addiction. The longer effects of KOR agonism (30 minutes or greater) have been linked to KOR-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by KOR-dependent modulation of dopamine, serotonin, or norepinephrine and/or via activation of downstream signal transduction pathways.