Probes for C-FOS

Abstract

Dopaminergic modulation of spinal cord plasticity has long been recognized but circuits affected by this system and the precise receptor subtypes involved in this modulation have not been defined. Dopaminergic modulation from the A11 nucleus of the hypothalamus contributes to plasticity in a model of chronic pain called hyperalgesic priming. Here we tested the hypothesis that the key receptor subtype mediating this effect is the D5 receptor (D5R). We find that a spinally-directed lesion of dopaminergic neurons reverses hyperalgesic priming in both sexes and that a D1/D5 antagonist transiently inhibits neuropathic pain. We used mice lacking D5Rs (DRD5KO mice) to show that carrageenan, interleukin 6 (IL-6) as well as brain derived neurotrophic factor (BDNF)-induced hyperalgesia and priming is reduced specifically in male mice. These male DRD5KO mice also show reduced formalin pain responses and decreased heat pain. To characterize the subtypes of dorsal horn neurons engaged by dopamine signaling in the hyperalgesic priming model we used c-fos labeling. We find that a mixed D1/D5 agonist given spinally to primed mice activates a subset of neurons in lamina III and IV of the dorsal horn that co-express PAX2, a transcription factor for GABAergic interneurons. In line with this, we show that gabazine, a GABA-A receptor antagonist, is antihyperalgesic in primed mice exposed to spinal administration of a D1/D5 agonist. Therefore, the D5R, in males, and the D1R, in females, exert a powerful influence over spinal cord circuitry in pathological pain likely via modulation of deep dorsal horn GABAergic neurons.

SIGNIFICIANCE STATEMENT: Pain is the most prominent reason why people seek medical attention and chronic pain incidence world-wide has been estimated to be as high as 33%. This study provides new insight into how descending dopamine controls pathological pain states. Our work demonstrates that dopaminergic spinal projections are necessary for the maintenance of a chronic pain state in both sexes, however, D5 receptors seem to play a critical role in males while females rely more heavily on D1 receptors, an effect which could be explained by sexual dimorphisms in receptor expression levels. Collectively our work provides new insights into how the dopaminergic system interacts with spinal circuits to promote pain plasticity.