127. B2-and B3-adrenergic receptors drive the development of COMT-dependent pain by increasing release of NO and innate immune cytokines

Decreased activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, contributes to pain in humans and animals. Previously, we demonstrated that development of COMT-dependent pain is mediated by B2- and B3-adrenergic receptors (B2- and B3ARs). Here, we investigated molecules downstream of B2- and B3ARs driving pain in animals with decreased COMT activity. Based on evidence linking role in pain and synthesis downstream of B2- and B3AR stimulation, we hypothesized nitric oxide (NO) and pro-inflammatory cytokines drive COMT-dependent pain. To test this, we measured plasma NO derivatives and cytokines in rats receiving the COMT inhibitor OR486 with or without the B2AR antagonist, ICI118,551 and B3AR antagonist, SR59320A. We also assessed if NO synthase inhibition and cytokine neutralization block the development of COMT-dependent pain. Results showed that animals receiving OR486 exhibited higher levels of NO derivatives, TNFα, IL-1β, IL-6, and CCL2 in a B2- and B3AR-dependent manner. Additionally, inhibition of NO synthases and neutralization of the innate immunity cytokines TNFα, IL-1β, and IL-6 blocked COMT-dependent pain development. Finally, we found that NO influences TNFα, IL-1β, IL-6 and CCL2 levels, while TNFα and IL-6 influence NO levels. Altogether, these results demonstrate that B2- and B3ARs contribute to COMT-dependent pain, at least partly, by increasing NO and cytokines. Furthermore, they identify B2- and B3ARs, NO, and pro-inflammatory cytokines as potential therapeutic targets for pain patients with COMT physiology abnormalities.