Chronic pain is one of the most prevalent medical conditions in the US. Besides physical symptoms, it has a profound impact on mental health and quality of life. The physiological mechanisms underlying chronic pain are complex; thus, treatments are limited. Opioid analgesics are one of the most commonly prescribed medications for the management of chronic pain; however, a major pitfall of the use of opioids is their addictive potential. Here we examine, in a mouse model, how chronic pain influences opioid addiction, with the hypothesis that chronic pain potentiates addiction due to the dual rewarding effects of opioids—euphoria and analgesia. We tested this using conditioned place preference (CPP), and find that this is not the case, as acquisition of a drug memory was attenuated under a chronic pain context. We also observe that chronic pain may facilitate extinction of the drug memory, suggesting that the mechanism of addiction under a chronic pain context is more complex than previously assumed. This complex behavioral phenotype is possibly a reflection of the underlying neural mechanisms involving multiple brain regions. In order to start understanding this mechanism, we mapped the expression of immediate early genes brain wide to identify key brain regions involved in both chronic pain and addiction. The prefrontal cortex (PFC) is one major brain region known to directly modulate circuits involved in both pain and drug addiction. However, the PFC consists of a myriad of cell types that project to distinct downstream targets, whose roles in specific behaviors are still largely unknown. A recent study classified the different subtypes of neurons in the PFC using single cell RNA sequencing (scRNA-seq), which identified a layer 5 pyramidal neuron (Pou3f1+) that is involved in pain and opioid taking. Using chemogenetic techniques, we manipulated the activity of Pou3f1+ neurons to test their response under pain and opioid use. These neurons appear to bi-directionally regulate pain perception, as activation increases mechanical sensitivity measured using von Frey filaments, and inhibition diminishes sensitivity. On the other hand, opioid administration under a chronic pain state potently activated Pou3f1+ neurons, as determined by cfos mRNA expression. These findings indicate potential interactions between the neural processing of chronic pain and opioid addiction, opening up the possibility of exploring common brain regions, and ultimately discrete cell types that can be therapeutically targeted to alleviate pain without the risk of addiction. / 2025-01-27T00:00:00Z
| Identifer | oai:union.ndltd.org:bu.edu/oai:open.bu.edu:2144/45532 |
| Date | 28 January 2023 |
| Creators | Badri, Madhulika |
| Contributors | Tornheim, Keith, Zhang, Yi |
| Source Sets | Boston University |
| Language | en_US |
| Detected Language | English |
| Type | Thesis/Dissertation |
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