EFFECT OF ACUTE PSILOCYBIN ON THERMAL AND NEUROPATHIC PAIN IN RODENTS
Authors: Canul *Martha Lopez , Nguyen Vivienne , Inserra Antonio , Nield Ella , Billings Hannah , Gobbi Gabriella 
Published: February 2025

Abstract

Background
Pain is a major health problem resulting in a high degree of suffering, physical, psychological and social impairments, and exorbitant health care costs1-2. Effective pain treatments are limited and are often accompanied by significant side effects3. Preclinical and clinical studies suggest that psychedelics, specifically psilocybin, can reset brain areas of functional connectivity that have a profound impact on central neuropathic states4. 5HT2A receptors have been implicated in both nociceptive pathways and the mechanism of action of psychedelics4. However, the effect of psychedelics on pain mechanisms is not fully understood.

Aim and Objectives
In this study, we examined the effect of psilocybin two models of pain: hot plate to investigate acute pain responses and the sciatic nerve ligation to assess the neuropathic pain antiallodynic responses.

Method
The hot plate test (HPT, Ugo Basile, Italy) was used to determine the acute thermal nociception. Mice (C57BL/6) were randomized and either veh (saline i.p.) or psilocybin (3 mg/kg i.p.) was administered. Mice were introduced to the hot plate at an initial temperature of 37° C with a near linear increase of 3° C per min. The nociceptive endpoint was established as the temperature eliciting a fast hind paw lick and/or paw withdrawal. To investigate chronic pain, we induced neuropathic pain (Sciatic Nerve Ligation) in Wistar rats. Neuropathy was determined using the von Frey (VF) filaments 14 days post-surgery. Animals who developed neuropathy were treated acutely with psilocybin (3 and 10 mg/kg, i.p.) or vehicle (saline, i.p.) and mechanical allodynia was assessed at time 0 (before administration), 0.5, 1, 2, 3, and 4 hours after administration.

Results
Acute systemic administration of psilocybin (3 mg/kg, i.p) did not increase thermal withdrawal threshold compared to vehicle-treated mice (t=0.4557, p= 0.6607, vehicle mean: 15.6 ± 2.657, n=5; psilocybin mean: 17.28 ± 2.556, n=5). On the other hand, in the NP model, psilocybin at the doses of 3 mg/kg and 10 mg/kg significantly increased mechanical withdrawal threshold compared to vehicle at time 0.5 hours (3mg/kg, p=0.0066, 10mg/kg, p=0.0012), 1 hour (3mg/kg, p=0.0043, 10mg/kg, p=0.0110), and 2 hours (3mg/kg, p=0.0051, 10mg/kg, p=0.0410), with no significant differences between doses of 3 and 10 mg (two-way ANOVA repeated measures, followed by Bonferroni’ s post-hoc test)

Discussion and Conclusion
These preliminary findings suggest that acute systemic administration of psilocybin has antiallodynic effect on NP, concurring with previous findings5-6, but demonstrates no nociceptive effect on acute thermal pain. Furthermore, this suggests that the action of psilocybin on pain reduction may specifically target NP, rather than generalized nociception of acute pain. Therefore, psilocybin may have a potential in the treatment neuropathic pain.

References
1.-Raffaeli, W., &Arnaudo, E. (2017). Pain as a disease: An overview. Journal of Pain Research, 10, 2003–2008. https://doi.org/10.2147/JPR.S138864
2.- Loeser, J. D., &Melzack, R. (1999). Pain: An overview. The Lancet, 353(9164), 1607–1609. https://doi.org/10.1016/S0140-6736(99)01311-2
3.-Curatolo, M., &Bogduk, N. (2001). Pharmacologic Pain Treatment of Musculoskeletal Disorders: Current Perspectives and Future Prospects. The Clinical Journal of Pain, 17(1), 25.
4.-Castellanos, J. P., Woolley, C., Bruno, K. A., Zeidan, F., Halberstadt, A., &Furnish, T. (2020). Chronic pain and psychedelics: A review and proposed mechanism of action. Regional Anesthesia &Pain Medicine, 45(7), 486–494. https://doi.org/10.1136/rapm-2020-101273
5.- Kolbman, N., Liu, T., Guzzo, P., Gilligan, J. P., Mashour, G. A., Vanini, G., &Pal, D. (2023). Intravenous psilocybin administration attenuates mechanical hypersensitivity in a rat model of chronic pain [Preprint]. Neuroscience. https://doi.org/10.1101/2023.08.26.554802
6.-Lyes, M., Yang, K. H., Castellanos, J., &Furnish, T. (2023). Microdosing psilocybin for chronic pain: A case series. Pain, 164(4), 698–702. https://doi.org/10.1097/j.pain.0000000000002778