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S.10.03 Vulnerability to drug addiction; significance of the mu-opioid receptor system
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S. 10 Endogenous opioids and addiction
a corresponding receptor by my and two US groups in the early 1970's. The following discovery of the enkephalins, pentapeptides with high affinity for these receptors made a large impact, since it offered a "toolbox" for studies into the mechanism of pain modulation, including clinical use of counter stimulation and other techniques derived from acupuncture, the subjective nature of clinical pain and the placebo effect, as well as the structure and actions of the reward system and the link to studies on drug dependence and alcoholism. This toolbox filled a niche in our approach to fundamental aspects of higher life forms, the need for self-protection and the urge for propagation of the species. In fact these systems were not only found in vertebrates but also in certain invertebrates suggesting an origin in early evolution of eukaryotes. Later work identified a complexity of the opioid systems. Modulation of pain and reward ("euphoria") are fundamental to the mu-receptor and the delta-receptor, with the enkephalins and betaendorphins as typical ligands. Whereas the enkephalins are easily degraded, beta-endorphin is more stable and may act at a distance setting an endogenous opioid tone. The complexity extends to the dynorphins which act on the kappa-receptor and nociceptin acting on the ORLl-receptor. These peptides have mixed actions depending on the site of release and may in fact modulate the actions of the enkephalins and beta-endorphin. Like so many other biological systems the pain modulatory and reward-generating signals are in turn matched by other modulatory systems. It is, however, well-known that endogenous control may capitulate and open up for drug dependence or alcoholism.
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Vulnerability to drug addiction; significance of the mu-opioid receptor system
M.A.F.M. Gerrits*, H.M.B. Lesscher, J.M. Van Ree. Rudolf Magnus Institute of Neuroscience, Dept. of Pharmacology and Anatomy, Utrecht, The Netherlands Pharmacological and genetic studies in humans have implicated a critical role of multiple biological systems in drug addiction. One such system, the endogenous opioid system, is central in mediating the dependence-creating properties of different legal and illegal addictive substances. It might therefore be suggested that individual (phenotypic or genotypic) differences that lead to functional differences in the endogenous opioid system may be of interest for the research into the vulnerability to addiction. Available data from animal self-administration studies so far also indicate a critical role of different biological systems in drug addiction. With respect to vulnerability to drug addiction, animal studies have indentified an important role of the mu-opioid receptor in the ventral tegmental area (VTA), where the cellbodies of the mesocorticolimbic dopamine system are located, in the sensitivity to drug reward [1]. Functionally, endogenous opioids have been shown to alter the firing of both dopaminergic and nondopaminergic (i.e. GABAergic) cells in the VTA. Activation of mu-opioid receptors, located on GABAergic neurons in the VTA, causes hyperolarization of these GABAergic neurons, thereby causing disinhibition of VTA dopaminergic neurons. This effect of mu-opioid receptor upon GABAergic neurotransmission is a likely mechanism for mu-opioid receptor modulation of drug reinforcement [2]. The mu-opioid receptor system (in the VTA) and its interaction with local neurotransmitter systems, particularly GABA and dopamine is important for the vulnerability to drug addiction.
References [1] Van Ree, J.M., Gerrits, M.A.F.M., Vanderschuren, L.J.M.J. (1999) Opioids, reward and addiction; an encounter of biology, psychology and medicine. Pharm. Rev. 51, 341 396. [2] Mathon, D.S., Lesscher, H.M.B., Gerrits, M.A.EM., Kamal, A., Pintar, J.E., Schuller, A.G.R, Spruijt, B.M., Burbach, J.P.H., Smidt, M.R, Van Ree, J.M., Ramakers, G.M.J. (2005) Increased GABAergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in ~t-opioid receptor knockout mice. Neuroscience 130, 359 367.
~ P E T
imaging of opioid release in the human brain
J-K. Zubieta 1 *, C.S. Stohler2. j University of Michigan, Mental
health Reserach Institute, Ann Arbot; USA," 2University of Matyland, School of Dentistty, USA The endogenous opioid system has been implicated in the effects of drugs of abuse, directly in the case of opiates, and indirectly for psychostimulants, alcohol, nicotine and THC. It is also a neurotransmitter system involved in responses to stress, therefore providing a link between the neurobiologies of stress and addiction. We have examined individual differences in the response of the endogenous opioid system and ~t-opioid receptors to understand factors underlying risk and resiliency for the development of opioid system associated pathologies. In this context, we utilized a model of moderate, sustained pain, as a physical and psychological stressor. In initial studies, the pain stressor activated ~t-opioid neurotransmission, as measured with PET and a selective ~t-opioid radiotracer in a number of cortical and subcortical regions, including some associated with responses to salient stimuli and reward. These included the anterior and dorsal cingulate cortex, prefrontal cortex, thalamus, nucleus accumbens, ventral pallidum, amygdala, hypothalamus and PAG. However, substantial interindividual variations in the regional response of the system were detected. Subsequent studies investigated the contribution of common genetic variants affecting catecholamine and opioid neurotransmission (e.g., COMT val 158met and A 118G ~t-opioid receptor polymorphisms). Sex differences and the effects of gonadal steroids were also examined, with prominent effects of both on the response of ~t-opioid neurotransmission to stress. These data demonstrate that the function of a stress and drug of abuse responsive system, the ~t-opioid, are modulated by common genetic polymorphisms and sex-related physiology.
References [1] Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Meyer CR, Koeppe RA, Stohler CS: Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 293:311 315, 2001. [2] Zubieta JK, Smith YR, Bueller JA, Xua Y, Woike TM, Kilbourn MR, Meyer CR, Koeppe RA, Stohler CS: Mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci 22: 510(~5107, 2002. [3] Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe KA, Stohler CS, Goldman D: COMT val158met genotype affects mu opioid neurotransmitter responses to a pain stressor. Science 299:124(~ 1243, 2003.
S. 10 Endogenous opioids and addiction
a corresponding receptor by my and two US groups in the early 1970's. The following discovery of the enkephalins, pentapeptides with high affinity for these receptors made a large impact, since it offered a "toolbox" for studies into the mechanism of pain modulation, including clinical use of counter stimulation and other techniques derived from acupuncture, the subjective nature of clinical pain and the placebo effect, as well as the structure and actions of the reward system and the link to studies on drug dependence and alcoholism. This toolbox filled a niche in our approach to fundamental aspects of higher life forms, the need for self-protection and the urge for propagation of the species. In fact these systems were not only found in vertebrates but also in certain invertebrates suggesting an origin in early evolution of eukaryotes. Later work identified a complexity of the opioid systems. Modulation of pain and reward ("euphoria") are fundamental to the mu-receptor and the delta-receptor, with the enkephalins and betaendorphins as typical ligands. Whereas the enkephalins are easily degraded, beta-endorphin is more stable and may act at a distance setting an endogenous opioid tone. The complexity extends to the dynorphins which act on the kappa-receptor and nociceptin acting on the ORLl-receptor. These peptides have mixed actions depending on the site of release and may in fact modulate the actions of the enkephalins and beta-endorphin. Like so many other biological systems the pain modulatory and reward-generating signals are in turn matched by other modulatory systems. It is, however, well-known that endogenous control may capitulate and open up for drug dependence or alcoholism.
•
Vulnerability to drug addiction; significance of the mu-opioid receptor system
M.A.F.M. Gerrits*, H.M.B. Lesscher, J.M. Van Ree. Rudolf Magnus Institute of Neuroscience, Dept. of Pharmacology and Anatomy, Utrecht, The Netherlands Pharmacological and genetic studies in humans have implicated a critical role of multiple biological systems in drug addiction. One such system, the endogenous opioid system, is central in mediating the dependence-creating properties of different legal and illegal addictive substances. It might therefore be suggested that individual (phenotypic or genotypic) differences that lead to functional differences in the endogenous opioid system may be of interest for the research into the vulnerability to addiction. Available data from animal self-administration studies so far also indicate a critical role of different biological systems in drug addiction. With respect to vulnerability to drug addiction, animal studies have indentified an important role of the mu-opioid receptor in the ventral tegmental area (VTA), where the cellbodies of the mesocorticolimbic dopamine system are located, in the sensitivity to drug reward [1]. Functionally, endogenous opioids have been shown to alter the firing of both dopaminergic and nondopaminergic (i.e. GABAergic) cells in the VTA. Activation of mu-opioid receptors, located on GABAergic neurons in the VTA, causes hyperolarization of these GABAergic neurons, thereby causing disinhibition of VTA dopaminergic neurons. This effect of mu-opioid receptor upon GABAergic neurotransmission is a likely mechanism for mu-opioid receptor modulation of drug reinforcement [2]. The mu-opioid receptor system (in the VTA) and its interaction with local neurotransmitter systems, particularly GABA and dopamine is important for the vulnerability to drug addiction.
References [1] Van Ree, J.M., Gerrits, M.A.F.M., Vanderschuren, L.J.M.J. (1999) Opioids, reward and addiction; an encounter of biology, psychology and medicine. Pharm. Rev. 51, 341 396. [2] Mathon, D.S., Lesscher, H.M.B., Gerrits, M.A.EM., Kamal, A., Pintar, J.E., Schuller, A.G.R, Spruijt, B.M., Burbach, J.P.H., Smidt, M.R, Van Ree, J.M., Ramakers, G.M.J. (2005) Increased GABAergic input to ventral tegmental area dopaminergic neurons associated with decreased cocaine reinforcement in ~t-opioid receptor knockout mice. Neuroscience 130, 359 367.
~ P E T
imaging of opioid release in the human brain
J-K. Zubieta 1 *, C.S. Stohler2. j University of Michigan, Mental
health Reserach Institute, Ann Arbot; USA," 2University of Matyland, School of Dentistty, USA The endogenous opioid system has been implicated in the effects of drugs of abuse, directly in the case of opiates, and indirectly for psychostimulants, alcohol, nicotine and THC. It is also a neurotransmitter system involved in responses to stress, therefore providing a link between the neurobiologies of stress and addiction. We have examined individual differences in the response of the endogenous opioid system and ~t-opioid receptors to understand factors underlying risk and resiliency for the development of opioid system associated pathologies. In this context, we utilized a model of moderate, sustained pain, as a physical and psychological stressor. In initial studies, the pain stressor activated ~t-opioid neurotransmission, as measured with PET and a selective ~t-opioid radiotracer in a number of cortical and subcortical regions, including some associated with responses to salient stimuli and reward. These included the anterior and dorsal cingulate cortex, prefrontal cortex, thalamus, nucleus accumbens, ventral pallidum, amygdala, hypothalamus and PAG. However, substantial interindividual variations in the regional response of the system were detected. Subsequent studies investigated the contribution of common genetic variants affecting catecholamine and opioid neurotransmission (e.g., COMT val 158met and A 118G ~t-opioid receptor polymorphisms). Sex differences and the effects of gonadal steroids were also examined, with prominent effects of both on the response of ~t-opioid neurotransmission to stress. These data demonstrate that the function of a stress and drug of abuse responsive system, the ~t-opioid, are modulated by common genetic polymorphisms and sex-related physiology.
References [1] Zubieta JK, Smith YR, Bueller JA, Xu Y, Kilbourn MR, Meyer CR, Koeppe RA, Stohler CS: Regional mu opioid receptor regulation of sensory and affective dimensions of pain. Science 293:311 315, 2001. [2] Zubieta JK, Smith YR, Bueller JA, Xua Y, Woike TM, Kilbourn MR, Meyer CR, Koeppe RA, Stohler CS: Mu-opioid receptor-mediated antinociceptive responses differ in men and women. J Neurosci 22: 510(~5107, 2002. [3] Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe KA, Stohler CS, Goldman D: COMT val158met genotype affects mu opioid neurotransmitter responses to a pain stressor. Science 299:124(~ 1243, 2003.