The mechanisms that lead to the maintenance of
chronic pain states are poorly understood, but their elucidation could lead to new insights into how
pain becomes chronic and how it can potentially be reversed. We investigated the role of spinal dorsal horn neurons and descending circuitry in plasticity mediating a transition to pathological
pain plasticity suggesting the presence of a
chronic pain state using hyperalgesic priming. We found that when dorsal horn
neurokinin 1 receptor-positive neurons or descending serotonergic neurons were ablated before hyperalgesic priming, IL-6- and
carrageenan-induced mechanical
hypersensitivity was impaired, and subsequent
prostaglandin E2 (
PGE2) response was blunted. However, when these neurons were lesioned after the induction of priming, they had no effect on the
PGE2 response, reflecting differential mechanisms driving plasticity in a primed state. In stark contrast, animals with a spinally applied dopaminergic lesion showed intact IL-6- and
carrageenan-induced mechanical
hypersensitivity, but the subsequent
PGE2 injection failed to cause mechanical
hypersensitivity. Moreover, ablating spinally projecting dopaminergic neurons after the resolution of the IL-6- or
carrageenan-induced response also reversed the maintenance of priming as assessed through mechanical
hypersensitivity and the mouse grimace scale. Pharmacological antagonism of spinal
dopamine D1/D5 receptors reversed priming, whereas D1/D5 agonists induced mechanical
hypersensitivity exclusively in primed mice. Strikingly, engagement of D1/D5 coupled with
anisomycin in primed animals reversed a
chronic pain state, consistent with reconsolidation-like effects in the spinal dorsal horn. These findings demonstrate a novel role for descending dopaminergic neurons in the maintenance of pathological
pain plasticity.