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 κ
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 κ
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.SIGNIFICANCE STATEMENT We show that KORs are sufficient to drive the tonic-aversive component of
chronic pain; the emotional component of
pain that is argued to significantly impact a patient's quality of life. The impact of our study is broadly relevant to
affective disorders associated with disruption of reward circuitry and thus likely contributes to many of the devastating sequelae of
chronic pain, including the poor response to treatment of many patients, debilitating
affective disorders (other disorders including anxiety and depression that demonstrate high comorbidity with
chronic pain) and
substance abuse. Indeed, coexisting psychopathology increases
pain intensity,
pain-related disability and effectiveness of treatments (Jamison and Edwards, 2013).