THE CEREBELLUM CONTRIBUTES TO CONDITIONED PAIN RELIEF PROCESSES IN AN ANIMAL MODEL OF NEUROPATHIC PAIN AND A HUMAN MODEL OF PLACEBO ANALGESIA

Pain reflects an integration of sensory, cognitive, and affective processes. The cerebellum is increasingly recognised as a contributor to pain, especially towards motivational-affective facets, including pain relief-related behaviours. Using an animal model, we examined preference to seek cannabidiol- or oxycodone-analgesia, and cerebellar cellular changes in female rats with chronic neuropathic pain. Neuropathic pain evoked allodynia, increased anxiety-like behaviour, and produced place preference for cannabidiol- and oxycodone-analgesia. Although oxycodone and cannabidiol differentially modulated cellular composition in the cerebellum, chronic neuropathic pain did not change the cerebellar density of calbindin-positive Purkinje cells or parvalbumin-positive interneurons. Subsequently, to explore functional cerebellar contributions to pain relief, we used ultra-high-field fMRI in a cohort of healthy adult participants to investigate cerebellar activation changes and cerebellar coupling associated with placebo analgesia responses. We identified regions of the posterior cerebellum in hemispheric lobule VI, Crus I, Crus II, lobule VIIIB and lobule X, as well as the brainstem pontine nuclei and ventral tegmental area, which were differentially activated between placebo responders and non-responders. We also found that during painful stimulation, regions involved in pain modulation, including the periaqueductal gray and parabrachial nucleus exhibited distinct synchrony with lobule VI/Crus I between responders and non-responders. VI-Crus I connectivity with pontine nuclei differed between responders and non-responders. Corroborating this, the strength of pain-specific connectivity between VI-Crus I and brainstem regions correlated with placebo analgesia magnitude. The posterior cerebellar contributions identified here reinforce that placebo analgesia is a complex phenomenon, and that the cerebellum plays a significant role in its presentation.