Ongoing projects

Of all medical illness, chronic pain is second only to bipolar disorder as a major cause of suicide, with risk factors that include pain severity, pain type, catastrophizing, poor sleep, perception of disability, and access to analgesics. Mood disorders are very common in patients with chronic pain, among whom depression has a prevalence as high as 80%. Such patients exhibit greater pain intensity, pain-related disability, and opioid misuse compared to those without a mood disorder (e.g. depression).

A potential strategy to alleviate negative affect associate with chronic pain is via antagonism of kappa opioid receptors (KORs). Administration of KOR drugs produces dysphoric and psychotomimetic effects in humans, elicits place aversion and depressive-like behaviors in pre-clinical models. We have shown that chronic pain upregulates KOR function in mesocorticolimbic circuitry, where it contributes to the affective, emotional component of pain. This project aims to determine the extent to which chronic pain changes KOR availability.

Significance: The significance of this project lies in its ability to demonstrate the involvement of KORs in limbic regions of brain in the response to chronic pain. Thereby, it will justify a focus on KOR as a therapeutic target in chronic pain, and can identify KOR availability in brain, measured by PET as a biomarker for pathology as well as for evaluating target engagement of relevant pharmaceuticals. Pilot data from this project will support our applications to NIH for funding provided through the HEAL initiative, a program to speed developments to combat the opioid crisis.

Mu opioid receptors (MORs) are densely expressed in different neurons throughout the brain. Some of these neurons are part of regions known to mediate reward. One such region is the striatum where MORs are densely expressed, yet the role of these MOR populations in modulating reward and analgesia is relatively unknown. We have begun to address this question by using a series of genetically engineered mouse lines in which MORs are deleted from neurons expressing receptors enriched in specific striatal neurons.

Significance: Mu opioid receptors mediate the effects of the commonly misused and prescribed opioids. These receptors are expressed in different neurons and pathways mediating reward. Although it is well-known that mu receptors in the midbrain regulate dopamine release and are important in mediating reward, little is known of the role of other populations that are expressed in the different neurons of the striatum, a hub of many reward pathways. In this study, we delete selective populations of these receptors in neurons of the striatum and study the effect of each deletion in reward-related and analgesic behaviors. Teasing apart the rewarding and analgesic properties of opioids is critical to mitigate abuse liability.

Our research aims to understand the mechanisms underlying opioid drug-dependent states. Such studies encompass assessment of neuroplastic changes in reward circuitry, including molecular and cellular changes within the mesolimbic dopaminergic system; processes established to contribute to addiction.

Chronic morphine administration results in significant gliosis, particularly in regions associated with reward, such as the VTA and nucleus accumbens. Currently, the mechanism by which non-neuronal cells, such as microglia, modulate reward circuitry is unclear.

Significance:: We discovered that microglia modulates reward circuitry and is correlated with release of brain derived neurotrophic factor (BDNF) that in turn alters chloride (Cl-) homeostasis in VTA neurons. We were the first to show that microglia may be a source of BDNF in the VTA, as both microglial and BDNF inhibitors recovered neuronal function and motivated behavior. This research includes novel, hypothesis-driven experiments to determine the contribution of microglial activation in opioid-induced adaptations of reward circuitry that contributes to incentive motivation that drives drug-seeking behavior.

Systems involved in pain processing and other affective and motivational systems interact extensively. Mood disorders such as depression are very common in chronic pain patients (up to 80%). It is consistently reported that co-morbid psychopathology in patients with chronic pain exhibit increased pain intensity and increased pain-related disability. Activation of the kappa opioid receptor (KOR) can produce anxiety and depressive symptoms in humans and preclinical models. Additionally, KOR drugs can produce dysphoric effects and hallucinogenic effects in humans.

One mechanism implicated in the aversive effects produced by KOR drugs is the modulation of mesolimbic dopamine circuitry. We, and others, have identified that mesolimbic circuitry dysfunction (including dopamine neurotransmission) precipitates mood disorders, impairs motivated behavior and likely contributes to chronic pain. Our premise is that KORs contribute to the negative emotional state associated with chronic pain and represents a therapeutic target to improve pain treatment and psychiatric outcomes.

Significance: The ACTTION-APS Pain Taxonomy recognizes the multidimensional and biopsychosocial nature of chronic pain, which is subject to comorbidities that impact the experience of chronic pain. Thus, capturing on-going pain and negative affective in chronic pain models are necessary for future analgesic drug development. Our research aims to understand how the kappa opioid system contributes to the affective dimension of pain. We expect our findings to have significant clinical translational potential to improve pain treatment and identify strategies to minimize opioid misuse.