Therapeutic efficacy and mechanisms of psilocybin for traumatic stress-induced anxiety and pain hypersensitivity - ABSTRACT Individuals with post-traumatic stress disorder (PTSD) experience chronic pain at significantly greater rates than the general population and greater pain intensity than those with chronic pain alone. Those with PTSD featuring comorbid pain suffer from higher rates of anxiety, depression, and opioid use disorder than those with just one of the conditions. Furthermore, trauma has been shown to enhance and prolong pain following injury. Clinical imaging studies and preclinical investigation reveal an overlap in the pathologic central nervous system changes that occur in PTSD and the transition from acute to chronic pain. Central to these changes is the nucleus accumbens (NAc), with both PTSD and chronic pain evidencing altered glutamatergic and midbrain monoaminergic afferent inputs to the NAc. Such findings suggest that the increased rate and severity of chronic pain among individuals with PTSD are due to trauma-induced neuroplastic changes in the NAc facilitating increased pain sensitivity. Accordingly, therapies that enhance neuroplasticity in the NAc may provide therapeutic benefits in chronic pain comorbid with PTSD by attenuating trauma-induced changes. We intend to test the therapeutic efficacy of the neuroplasticity-enhancing agent, psilocybin, in an animal model of trauma- induced anxiety and hyperalgesia using a well-established animal model of PTSD. We hypothesize that the psilocybin intervention will attenuate pain and anxiety symptoms by mitigating trauma-induced changes in the NAc via the same mechanism of enhancing oxytocin-mediated neuroplasticity in the NAc by which psilocybin improves social reward learning. We will gather translationally relevant preclinical evidence on this hypothesis with a rat model of traumatic injury, which couples a thermal burn injury model with the procedure known as single prolonged stress (SPS), wherein rats are exposed to three stressors in a single session: immobilization, group forced swim, and ether exposure. SPS is the favored preclinical PTSD model due to its capacity to reliably induce a phenotype that satisfies all DSM-5 and model validity criteria. Critically, SPS on its own also induces pain sensitivity in rats. The therapeutic efficacy of psilocybin intervention will be evaluated using well-defined behavioral assays of anxiety and pain sensitivity, and psilocybin-induced NAc molecular changes will be assessed by qPCR. Using a chemogenetic approach, we will test whether oxytocinergic projections from the paraventricular nucleus (PVN) to the NAc are required for psilocybin’s therapeutic efficacy in this model and how such inputs modulate psilocybin-induced changes in the expression of neuroplasticity and neuromodulator- related genes in the NAc. This project will provide translational evidence of the therapeutic mechanism of psilocybin for PTSD and comorbid pain. Such data will enhance our understanding of the treatment of PTSD and its comorbidities and may aid in the design of novel therapeutic compounds and approaches for this debilitating pathology currently suffering from inadequate treatment options.
