title: Persistent pain facilitates response to morphine reward by downregulation of central amygdala GABAergic function.
abstract: Opioid-based analgesics are widely used for treating chronic pain, but opioids are highly addictive when repeatedly used because of their strong rewarding effects. In recent years, abuse of prescription opioids has dramatically increased, including incidences of misuse of opioid drugs prescribed for pain control. Despite this issue in current clinical pain management, it remains unknown how pain influences the abuse liability of prescription opioids. Pain as aversive experience may affect opioid reward of positive emotion through common brain sites involved in emotion processing. In this study, on a rat model of chronic pain, we determined how persistent pain altered behavioral responses to morphine reward measured by the paradigm of unbiased conditioned place preference (CPP), focusing on GABAergic synaptic activity in neurons of the central nucleus of the amygdala (CeA), an important brain region for emotional processing of both pain and reward. We found that pain reduced the minimum number of morphine-conditioning sessions required for inducing CPP behavior. Both pain and morphine conditioning that elicited CPP inhibited GABA synaptic transmission in CeA neurons. Pharmacological activation of CeA GABAA receptors reduced the pain and inhibited CPP induced both by an effective dose of morphine and by a sub-threshold dose of morphine under pain condition. Furthermore, inhibition of CeA GABAA receptors mimicked the pain effect, rendering the sub-threshold dose of morphine effective in CPP induction. These findings suggest that pain facilitates behavioral responses to morphine reward by predisposing the inhibitory GABA function in the CeA circuitry involved in the behavior of opioid reward.
authors.affiliation: 1] Department of Anesthesiology and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA [2] Department of Neurobiology and Biophysics, Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Neurobiology and Biophysics, Key Laboratory of Brain Functions and Diseases, School of Life Science, University of Science and Technology of China, Hefei, China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Tao
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yuan-Yuan
authors.initials: YY
authors.lastname: Hou
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas Health Science Center at Houston, Houston, TX, USA.
authors.forename: Yun-Gang
authors.initials: YG
authors.lastname: Lu
authors.affiliation: Department of Anesthesiology and Pain Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Zhizhong Z
authors.initials: ZZ
authors.lastname: Pan
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D066274:Central Amygdaloid Nucleus / Q000187:drug effects* / Q000503:physiopathology; D059350:Chronic Pain / Q000188:drug therapy* / Q000503:physiopathology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D005620:Freund's Adjuvant; D006614:Hindlimb; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D008562:Membrane Glycoproteins; D009020:Morphine / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011897:Random Allocation; D017208:Rats, Wistar; D011963:Receptors, GABA-A / Q000378:metabolism; D017472:Receptors, Interleukin-1; D012201:Reward; D013028:Space Perception / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D000701:Analgesics, Opioid; D008562:Membrane Glycoproteins; D011963:Receptors, GABA-A; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; D005680:gamma-Aminobutyric Acid; D009020:Morphine; D005620:Freund's Adjuvant