期刊
JOURNAL OF NEUROSCIENCE
卷 39, 期 21, 页码 4162-4178出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0274-19.2019
关键词
aversion; chronic pain; dopamine; emotion; negative affect; opiate
资金
- University of California Irvine
- Shirley and Stefan Hatos Foundation
- NIH [DA005010, K99DA040016]
- Canadian Institutes of Health Research [MOP 123298, MOP133523]
- Cousins Center for Psychoneuroimmunology
- UCI Graduate Division Public Impact Fellowship
- School of Medicine Outstanding Student Fellowship
- Basque Government
Pain is a multidimensional experience and negative affect, or how much the pain is bothersome, significantly impacts the sufferers' quality of life. It is well established that the kappa opioid system contributes to depressive and dysphoric states, but whether this system contributes to the negative affect precipitated by the occurrence of chronic pain remains tenuous. Using a model of persistent pain, we show by quantitative real-time-PCR, florescence in situ hybridization, Western blotting and GTPgS autoradiography an upregulation of expression and the function of kappa opioid receptors (KORs) and its endogenous ligand dynorphin in the mesolimbic circuitry in animals with chronic pain compared with surgical controls. Using in vivo microdialysis and microinjection of drugs into the mesolimbic dopamine system, we demonstrate that inhibiting KORs reinstates evoked dopamine release and reward-related behaviors in chronic pain animals. Chronic pain enhanced KOR agonist-induced place aversion in a sex-dependent manner. Using various place preference paradigms, we show that activation of KORs drives pain aversive states in male but not female mice. However, KOR antagonist treatment was effective in alleviating anxiogenic and depressive affective-like behaviors in both sexes. Finally, ablation of KORs from dopamine neurons using AAV-TH-cre in KORloxP mice prevented pain-induced aversive states as measured by place aversion assays. Our results strongly support the use of KOR antagonists as therapeutic adjuvants to alleviate the emotional, tonic-aversive component of chronic pain, which is argued to be the most significant component of the pain experience that impacts patients' quality of life.
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