Post by Elisa Guma
What's the science?
Chronic pain is a multidimensional experience. It is one of the leading causes of suicide, and often co-occurs with mood disorders such as depression and anxiety. Activation of the kappa opioid system is implicated in mood disorders like depression and has been shown to produce negative emotions, however its role in emotion associated with chronic pain remains unclear. This week in the Journal of Neuroscience, Liu and colleagues used a mouse model of chronic pain to investigate the function of the kappa opioid receptor (KOR) system in the mesolimbic circuitry (including the nucleus accumbens and ventral tegmental area) in modulating the aversive (i.e. emotional) component of chronic pain.
How did they do it?
The authors first examined the behavioural relationship between KOR activation and chronic pain; they used the conditioned-place-preference/aversion paradigm to test for preference (more time spent in drug-paired environment) or aversion (more time spent in control environment) to a KOR agonist (a receptor activator) and a long-lasting KOR antagonist (an inhibitor), in mice with peripheral nerve injury to their hind leg (a model of chronic neuropathic pain).
Next, the authors tested the extent to which chronic pain alters expression and function of KORs, and expression of the endogenous ligand dynorphin, which binds to KOR in the mesolimbic circuitry of the brain. They did this by measuring ex vivo expression of messenger RNA (using in situ hybridization) and binding potential of KORs (autoradiography). Dopamine circuitry is thought to be dysfunctional in chronic pain. Therefore, using in vivo microdialysis, the authors measured dopamine release in real-time following morphine administration in the mesolimbic circuitry, to test the relationship between KORs and the mesolimbic dopamine system. To further characterize this relationship, the authors stained for KOR messenger RNA levels in dopamine cells projecting from the ventral tegmental area to the nucleus accumbens.
The authors investigated the effects of an opioid antagonist (naloxone) with or without a KOR antagonist pretreatment, on preference and aversion. Because naloxone is non-selective (i.e. binds to receptors other than KORs), they used mice whose pro-enkephalin gene (another endogenous opioid) was knocked out to isolate the role of KORs. They also used the conditioned place preference/ aversion model to assess ongoing pain aversion to determine if KORs contribute to this aversive state. They performed some of these experiments in a model of chronic inflammatory pain to confirm that their findings were applicable to chronic pain more generally. Lastly, to investigate the specific role of KORs in the mesolimbic system, they selectively knocked out KORs in dopamine neurons projecting from the VTA (using adeno-associated virus technology) and measured conditioned place preference and aversion.
What did they find?
Opioid agonist administration produced a dose-dependent place aversion in male but not female mice who had chronic pain. Male (but not female) mice also had a profound increase in KOR messenger RNA expression, KOR activation (based on autoradiography), and phosphorylated KOR protein levels in the nucleus accumbens contralateral to the peripheral nerve injury. Pro-dynorphin (an opioid polypeptide found in the body) levels were increased in both male and female pain mice. These findings suggest that chronic pain associated with peripheral nerve injury increases expression and activation of the KORs in the nucleus accumbens of male but not female mice.
Micro-dialysis experiments demonstrated that systemic morphine administration failed to induce an increase in dopamine release in mice experiencing chronic pain. However, when KORs were blocked, dopamine release was normalized, suggesting that KORs act to downregulate dopamine release and the pain-reducing effects of morphine. Similarly, injection of mu-opioid agonist directly into the ventral tegmental area (in this experiment in rats) did not induce the expected conditioned place preference in rats with chronic pain. The conditioned place preference was restored in rats with chronic pain when KORs were blocked by an antagonist, suggesting that KORs antagonists restore blunted reward-related processing in chronic pain. Further, elevated KOR messenger RNA levels were observed in reward circuitry dopamine neurons (which send signals from the ventral tegmental area to the nucleus accumbens) of male mice, suggesting that chronic neuropathic pain causes a sex-dependent increase in KOR expression and function.
Administration of the opioid antagonist naloxone produced aversion in both pain naïve wild-type mice and in wild-type mice experiencing chronic pain. Interestingly, it produced place preference in chronic pain pro-enkephalin knockout mice, and this was prevented by a long-acting opioid antagonist. These experiments suggest that naloxone-induced conditioned place preference in chronic pain pro-enkephalin knockout mice, is specifically associated with KOR blockade by naloxone. The authors found similar effects using an inflammatory pain model. Finally, they showed that place aversion was absent in mice whose KOR had been conditionally knocked out in dopamine neurons of the ventral tegmental area. This suggests that KORs in dopamine mesolimbic circuits contribute to aversive component of pain.
What's the impact?
This study shows that activation of the kappa opioid receptor system in the reward circuitry of the brain is responsible for driving the negative emotional (tonic-aversive) component of pain in a sex-dependent manner. Further, the mechanisms investigated here are relevant to affective disorders associated with a disruption in reward circuitry, such as anxiety and depression as well as substance abuse. Kappa opioid antagonists may be a promising treatment avenue for these individuals, possibly reducing prescription opioid misuse in patient populations.
Liu et al. Kappa Opioid Receptors Drive a Tonic Aversive Component of Chronic Pain. The Journal of Neuroscience (2019). Access the original scientific publication here.