The FDA-approved compound, pramipexole and the clinical-stage investigational drug, dexpramipexole, reverse chronic allodynia from sciatic nerve damage in mice, and alter IL-1ß and IL-10 expression from immune cell culture.

ABSTRACT

During the onset of neuropathic pain from a variety of etiologies, nociceptors become hypersensitized, releasing neurotransmitters and other factors from centrally-projecting nerve terminals within the dorsal spinal cord. Consequently, glial cells (astrocytes and microglia) in the spinal cord are activated and mediate the release of proinflammatory cytokines that act to enhance pain transmission and sensitize mechanical non-nociceptive fibers which ultimately results in light touch hypersensitivity, clinically observed as allodynia. Pramipexole, a D2/D3 preferring agonist, is FDA-approved for the treatment of Parkinson's disease and demonstrates efficacy in animal models of inflammatory pain. The clinical-stage investigational drug, R(+) enantiomer of pramipexole, dexpramipexole, is virtually devoid of D2/D3 agonist actions and is efficacious in animal models of inflammatory and neuropathic pain. The current experiments focus on the application of a mouse model of sciatic nerve neuropathy, chronic constriction injury (CCI), that leads to allodynia and is previously characterized to generate spinal glial activation with consequent release IL-1ß. We hypothesized that both pramipexole and dexpramipexole reverse CCI-induced chronic neuropathy in mice, and in human monocyte cell culture studies (THP-1 cells), pramipexole prevents IL-1ß production. Additionally, we hypothesized that in rat primary splenocyte culture, dexpramixole increases mRNA for the anti-inflammatory and pleiotropic cytokine, interleukin-10 (IL-10). Results show that following intravenous pramipexole or dexpramipexole, a profound decrease in allodynia was observed by 1 hr, with allodynia returning 24 hr post-injection. Pramipexole significantly blunted IL-1ß protein production from stimulated human monocytes and dexpramipexole induced elevated IL-10 mRNA expression from rat splenocytes. The data support that clinically-approved compounds like pramipexole and dexpramipexole support their application as anti-inflammatory agents to mitigate chronic neuropathy, and provide a blueprint for future, multifaceted approaches for opioid-independent neuropathic pain treatment.