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The orexin 1 receptor modulates kappa opioid receptor function via a JNK-dependent mechanism.

ABSTRACT: The orexin 1 receptor (OX1R) and the kappa opioid receptor (KOR) are two G protein-coupled receptors (GPCRs) previously demonstrated to play important roles in modulating the rewarding effects of drugs of abuse such as cocaine. Using cells heterologously expressing both receptors, we investigated whether OX1R can regulate the function of KOR and vice versa. Activation of OX1R was found to attenuate agonist-activated KOR-mediated inhibition of cAMP production. In contrast, agonist-activated KOR-mediated β-arrestin recruitment and p38 activation were enhanced in the presence of activated OX1R. These effects are independent of OX1R internalization but are blocked in the presence of the JNK inhibitor SP-600125. OX1R signaling does not affect ligand binding by KOR. Taken together, these data suggest that OX1R signaling can modulate KOR function in a JNK-dependent manner, promoting preferential signaling of KOR via β-arrestin/p38 rather than Gαi. Conversely, Gαq coupling of OX1R is unaffected by activation of KOR, suggesting that this crosstalk is unidirectional. Given that KOR Gαi-mediated signaling events and β-arrestin-mediated signaling events are thought to promote distinct cellular responses and physiological outcomes downstream of KOR activation, this mechanism may have important implications on the behavioral effects of KOR activity.

SUBMITTER: Robinson JD

PROVIDER: S-EPMC5549559 | biostudies-other | 2015 Jul

REPOSITORIES: biostudies-other

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Project description:Behavioral, biological, and social sequelae that lead to drug addiction differ between men and women. Our efforts to understand addiction on a mechanistic level must include studies in both males and females. Stress, anxiety, and depression are tightly linked to addiction, and whether they precede or result from compulsive drug use depends on many factors, including biological sex. The neuropeptide dynorphin (DYN), an endogenous ligand at kappa opioid receptors (KORs), is necessary for stress-induced aversive states and is upregulated in the brain after chronic exposure to drugs of abuse. KOR agonists produce signs of anxiety, fear, and depression in laboratory animals and humans, findings that have led to the hypothesis that drug withdrawal-induced DYN release is instrumental in negative reinforcement processes that drive addiction. However, these studies were almost exclusively conducted in males. Only recently is evidence available that there are sex differences in the effects of KOR activation on affective state. This review focuses on sex differences in DYN and KOR systems and how these might contribute to sex differences in addictive behavior. Much of what is known about how biological sex influences KOR systems is from research on pain systems. The basic molecular and genetic mechanisms that have been discovered to underlie sex differences in KOR function in pain systems may apply to sex differences in KOR function in reward systems. Our goals are to discuss the current state of knowledge on how biological sex contributes to KOR function in the context of pain, mood, and addiction and to explore potential mechanisms for sex differences in KOR function. We will highlight evidence that the function of DYN-KOR systems is influenced in a sex-dependent manner by: polymorphisms in the prodynorphin (pDYN) gene, genetic linkage with the melanocortin-1 receptor (MC1R), heterodimerization of KORs and mu opioid receptors (MORs), and gonadal hormones. Finally, we identify several gaps in our understanding of "if" and "how" DYN and KORs modulate addictive behavior in a sex-dependent manner. Future work may address these gaps by building on the mechanistic studies outlined in this review. Ultimately this will enable the development of novel and effective addiction treatments tailored to either males or females.

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The orexin 1 receptor modulates kappa opioid receptor function via a JNK-dependent mechanism.

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