Investigating the Cortical Action of Psilocybin in Chronic Pain

University Of Pennsylvania, Philadelphia PA

Investigators

Abstract

Project Summary/Abstract A dire need for novel chronic pain treatments has arisen due to the opioid crisis and the closure of opioid- prescribing pain clinics, affecting over 50 million US adults. The psychedelic serotonin 2a/c receptor (5HT2a/cR) agonist psilocybin has shown preliminary efficacy in treating various chronic pain disorders, such as cluster headaches, fibromyalgia, cancer pain, and back pain. However, its mechanisms are still unknown. One hypothesis is that psilocybin induces corrective neuroplasticity downstream of 5HT2Rs. While the role of cortical 5HT2aRs in neuroplasticity is known, 5HT2aR activation by psychedelics induces hallucinations, complicating clinical applications. In contrast, cortical 5HT2cR is non-hallucinogenic and anti-addictive, making it a potentially valuable pharmacological target. Although these receptors are Gq-coupled and excitatory in some regions, cortical 5HT2cRs are inhibitory due to their coupling with potassium channels. Recently, I established a role for psilocybin-induced inhibition of retrosplenial cortex (RSC) neurons responsive to an electrical foot shock in mice in enhanced fear extinction. The RSC is one of the few cortical regions expressing 5HT2cRs on Camk2a- expressing pyramidal neurons, which undergo significant transcriptional, morphological, and dynamic changes in chronic pain. Chemogenetic inhibition of these neurons in mice can reduce mechanical hyperalgesia, while excitation enhances it after spared nerve injury (SNI)-induced chronic pain, as can a single dose of 1mg/kg of psilocybin. Therefore, I hypothesize that psilocybin ameliorates chronic pain by altering the encoding of pain in the RSC (Aim 1) via 5HT2cR stimulation (Aim 2a) and inhibition of excitatory 5HT2cR+ neurons (Aim 2b). In Aim 1, I will perform one-photon calcium imaging to investigate the effects of psilocybin on encoding spontaneous pain behaviors acutely, 24 hours post-acutely, and 1 week post-acutely in SNI mice. In Aim 2a, I will perform intracranial pharmacology studies to determine the necessity and sufficiency of intra-RSC 5HT2cR stimulation for psilocybin-ameliorated chronic pain. Finally, in Aim 2b, I will chemogenetically manipulate 5HT2cR+ RSC neurons to determine if inhibition of these neurons is sufficient to replicate some or all effects of psilocybin. Successful completion of these aims will provide (1) the first description of the effect of psilocybin and chronic pain on naturalistic single-cell dynamics and (2) elucidate the role of cortical 5HT2cRs and 5HT2cR+ cells in chronic pain relief, laying the foundation for future efforts to improve the viability of psilocybin pain therapy. The applicant, Sophie Rogers, will receive advanced training in neurobehavioral deep-learning pain assays, intracranial pharmacology and chemogenetics, transgenic approaches, single-cell calcium imaging, experimental design and statistics, and computational analysis of high-dimensional neural datasets from her Co- Mentors Drs. Gregory Corder and Maria Geffen. This NRSA F31 training will support the applicant’s current and future research goals and enable her to impact basic neuroscience research as an independent researcher.