NEUROBIOLOGY OF OPIOIDS
Opioid Receptors: The Basis of Pain Relief and Addiction
Mary Jeanne Kreek, M.D.
Pain is modulated by endogenous opioid peptides, and exogenous opioids are effective analgesic agents. Many drugs of abuse act directly on or affect the endogenous opioid system. The µ-opioid receptor and related endorphins modulate many physiological functions, including the hypothalamic-pituitary-adrenal stress responsive system. In positron emission tomography studies, we have shown that the highest density of µ-opioid receptors is in the thalamus and regions of dopaminergic terminals, including the amygdala, insula, anterior cingulate, caudate, and putamen. We have also shown that the long-acting opioid methadone, used in the treatment of opiate addiction, leads to only modest (20–30 percent) occupancy, and facilitates the normalization of functions modulated by the endogenous opioid system that are disrupted during heroin use, such as stress responsivity. We use a bidirectional translational research approach to develop novel animal models to study the molecular, neurobiological, and behavioral impact of opiate and other addictions. Our longstanding hypothesis, that atypical responsivity to stress and stressors contributes to the acquisition, persistence, and relapse to opiate and cocaine addiction and alcoholism, has been confirmed. Our team identifies a common variant of the µ-opioid receptor gene, A118G, and shows that it is functional, with the resulting receptor having three times greater affinity and signal transduction when ß-endorphin is the binding ligand. We hypothesize and show that the presence of this functional variant results in basal and challenge differences in stress responsive hormones, predicts a positive outcome to the treatment of alcoholism with opioid antagonists, and is associated with alcoholism and opiate addiction.
Opiate Analgesics: Pathways to Addiction
Christopher J. Evans, Ph.D.
Opioid drugs have high addictive potential, and the misuse of opioid painkillers has escalated alarmingly in recent years. Although opioids are effective analgesics, these drugs can be profoundly euphoric, and continued use results in neuroadaptive mechanisms that oppose the acute effects and that undoubtedly contribute to maintained drug-taking and the need for increased amounts of the drug to ensure therapeutic efficacy. We discuss compensatory neuroadaptive mechanisms and present data showing that chronic, morphine-induced hyperalgesia depends on the pain modality. There are multiple opioid alkaloid drugs available for the treatment of pain, and one goal of this presentation is to highlight the opioid drug properties and pharmacologic mechanisms that address issues of safety, reduced euphoria, and the mechanisms involved with adaptive processes. Some of these properties concern differences in intrinsic activity, receptor selectivity, and pharmacodynamics. However, basic research has now revealed a pharmacological complexity of opioid drug–receptor interactions that requires us to consider every opioid drug as potentially unique with regard to receptor signaling, trafficking, and desensitization. Opioid receptors are now viewed as components of dynamic heterogeneous protein complexes that are orchestrated by ligand interactions, providing the expanded potential for differential actions mediated via the same opioid receptor protein.
Pain and Addiction: Can We Actually See the Relationships?
Jon-Kar Zubieta, M.D., Ph.D.
Two neurotransmitters involved with the effects of opiates and other drugs of abuse (the dopaminergic and opioid), are likely to represent a point of confluence between the neurobiologies of pain and addiction. We present a series of studies in humans, focusing on the response of these systems to sustained pain. µ-Opioid and dopamine (DA) D2 receptors are quantified at baseline and during pain in healthy subjects using external imaging techniques (i.e., positron emission tomography and selective DA D2 and µ-opioid receptor radiotracers). Data are presented on the involvement of these neurotransmitter systems in the experience of pain as well as the initial evidence of their dysregulation in chronic pain conditions. We discuss the implications of the interindividual differences in DA D2 and µ-opioid receptor availability and in the capacity to activate these neurotransmitter systems. They are discussed in the context of the contributions of sex, gonadal steroids, common genetic polymorphisms, and cognitive factors. Based on these data, variations in the function of DA and opioid systems in response to pain, a physical and emotional stressor, are proposed to underlie varying risks for the initiation of drug use and the development of addiction in the context of persistent clinical pain.