Obara, I. and Goulding, S.P. and Gould, A.T. and Lominac, K.D. and Hu, J.H. and Zhang, P.W. and von Jonquieres, G. and Dehoff, M. and Xiao, B. and Seeburg, P.H. and Worley, P.F. and Klugmann, M. and Szumlinski, K.K. (2013) 'Homers at the interface between reward and pain.', Frontiers in psychiatry., 4 . p. 39.
Pain alters opioid reinforcement, presumably via neuroadaptations within ascending pain pathways interacting with the limbic system. Nerve injury increases expression of glutamate receptors and their associated Homer scaffolding proteins throughout the pain processing pathway. Homer proteins, and their associated glutamate receptors, regulate behavioral sensitivity to various addictive drugs. Thus, we investigated a potential role for Homers in the interactions between pain and drug reward in mice. Chronic constriction injury (CCI) of the sciatic nerve elevated Homer1b/c and/or Homer2a/b expression within all mesolimbic structures examined and for the most part, the Homer increases coincided with elevated mGluR5, GluN2A/B, and the activational state of various down-stream kinases. Behaviorally, CCI mice showed pain hypersensitivity and a conditioned place-aversion (CPA) at a low heroin dose that supported conditioned place-preference (CPP) in naïve controls. Null mutations of Homer1a, Homer1, and Homer2, as well as transgenic disruption of mGluR5-Homer interactions, either attenuated or completely blocked low-dose heroin CPP, and none of the CCI mutant strains exhibited heroin-induced CPA. However, heroin CPP did not depend upon full Homer1c expression within the nucleus accumbens (NAC), as CPP occurred in controls infused locally with small hairpin RNA-Homer1c, although intra-NAC and/or intrathecal cDNA-Homer1c, -Homer1a, and -Homer2b infusions (to best mimic CCI's effects) were sufficient to blunt heroin CPP in uninjured mice. However, arguing against a simple role for CCI-induced increases in either spinal or NAC Homer expression for heroin CPA, cDNA infusion of our various cDNA constructs either did not affect (intrathecal) or attenuated (NAC) heroin CPA. Together, these data implicate increases in glutamate receptor/Homer/kinase activity within limbic structures, perhaps outside the NAC, as possibly critical for switching the incentive motivational properties of heroin following nerve injury, which has relevance for opioid psychopharmacology in individuals suffering from neuropathic pain.
|Keywords:||Homer proteins, Group1 metabotropic glutamate receptors, NMDA receptors, Neuropathic pain, Heroin, Nucleus accumbens, Conditioned place-preference, Conditioned place-aversion.|
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|Publisher Web site:||http://dx.doi.org/10.3389/fpsyt.2013.00039|
|Publisher statement:||Copyright: © 2013 Obara, Goulding, Gould, Lominac, Hu, Zhang, von Jonquieres, Dehoff, Xiao, Seeburg, Worley, Klugmann and Szumlinski. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.|
|Record Created:||07 Apr 2014 11:35|
|Last Modified:||09 Sep 2014 16:36|
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