Background & Aims
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 the 5-HT2A receptor agonist psilocybin, can ‘reset’ functional connectivity in brain areas, which have a profound impact on central neuropathic states4. Moreover, 5HT2A receptors are implicated in both nociceptive pathways and the mechanism of action of psychedelics4. However, the effect of psychedelics on pain mechanisms is not yet fully understood. In this study, we examined the effect of psilocybin on acute and chronic pain thresholds.
Methods
Mice (C57BL/6) and rats (Wistar) were housed in standardized animal facilities. Acute thermal nociception was measured using the Hot Plate Test (HPT, Ugo Basile, Italy) in mice. Initial temperature was set at 37°C with a near linear increase of 3°C per min. Nociception was established as the temperature eliciting a fast hind paw withdrawal. Formalin 1 % was administrated subcutaneously in the dorsal mid-plantar surface of mice hind paw and pain-related behaviour (licking, kicking, and shaking) was recorded7 at 5-min intervals for 60 min and separated in phase-1 (0-10 min) and phase-2 (15 to 60 min). Lastly, neuropathic pain in rats was induced with L5-L6 nerve ligation model8. 14 days after surgery, mechanical allodynia was evaluated using the von Frey (VF) filaments. Allodynic animals were administered either vehicle or psilocybin and assessed with VF from 0 to 4 hours after treatment. For all settings, vehicle or psicybin (3 mg/kg i.p.) was administered 10 min before each test.
Results
The psilocybin treated mice (3 mg/kg, i.p) vs vehicle-treated mice in the HPT showed no difference in the thermal withdrawal threshold (T-test, t=1.618, p= 0.127, vehicle: 38.2 ± 0.21; psilocybin: 38.6 ± 0.12, n=10 per group). In the formalin test, the Area Under the Curve (AUC) for both phases (nociceptive and inflammatory) showed a significant reduction of nocifensive behavior induced by psylocibin vs vehicle treated animals (phase-1 p<0.01; phase-2 p<0.001, n=10 per group). Additionally, in neuropathic rats, the analysis of the mechanical allodynia measured with VF filament, showed no interaction effect (interaction F(10,60)= 1.884, P=0.0653, two -way ANOVA RM), but a significant main effects of treatment (F(5,60)= 5.150, P= 0.0005) and time (F(2,12)= 15.39, P=0.0005, n=8-10 per group). Post-hoc analysis showed that psilocybin significantly increased mechanical withdrawal threshold compared to vehicle at time 0.5 hours (p=0.0066), 1 hour (p=0.0043), and 2 hours (p=0.0051).
Conclusions
In conclusion, this study demonstrate that the acute systemic administration of psilocybin has an analgesic effect on chemically-induced persistent pain and chronic neuropathic pain but not on acute thermal nociception, in agreement with previous findings5-6. Therefore, psilocybin may be a potential treatment in certain pain conditions. Furthermore, this suggests that the action of psilocybin on pain reduction may specifically target persistent and long-lasting pain, rather than acute 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.
7.Dubuisson D, Dennis SG. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain. 1977 Dec;4(2):161-174. doi: 10.1016/0304-3959(77)90130-0. PMID: 564014. DOI: 10.1016/0304-3959(77)90130-0
8.Kim, S. H., & Chung, J. M. (1992). An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain, 50(3), 355–363. https://doi.org/10.1016/0304-3959(92)90041-9
Presenting Author
Martha Lopez-Canul
Poster Authors
Topics
- Treatment/Management: Interventional Therapies – Other