title: β2- and β3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines.
abstract: 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 both β2- and β3-adrenergic receptors (β2ARs and β3ARs). Here we investigated molecules downstream of β2- and β3ARs driving pain in animals with decreased COMT activity. Based on evidence linking their role in pain and synthesis downstream of β2- and β3AR stimulation, we hypothesized that nitric oxide (NO) and proinflammatory cytokines drive COMT-dependent pain. To test this, we measured plasma NO derivatives and cytokines in rats receiving the COMT inhibitor OR486 in the presence or absence of the β2AR antagonist ICI118,551+β3AR antagonist SR59320A. We also assessed whether the NO synthase inhibitor L-N(G)-nitroarginine methyl ester (L-NAME) and cytokine-neutralizing antibodies block the development of COMT-dependent pain. Results showed that animals receiving OR486 exhibited higher levels of NO derivatives, tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), interleukin-6 (IL-6), and chemokine (C-C motif) ligand 2 (CCL2) in a β2- and β3AR-dependent manner. Additionally, inhibition of NO synthases and neutralization of the innate immunity cytokines TNFα, IL-1β, and IL-6 blocked the development of COMT-dependent pain. Finally, we found that NO influences TNFα, IL-1β, IL-6, and CCL2 levels, whereas TNFα and IL-6 influence NO levels. Altogether, these results demonstrate that β2- and β3ARs contribute to COMT-dependent pain, at least partly, by increasing NO and cytokines. Furthermore, they identify β2- and β3ARs, NO, and proinflammatory cytokines as potential therapeutic targets for pain patients with abnormalities in COMT physiology.
authors.affiliation: Center for Pain Research and Innovation, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Hartung
authors.forename: Brittney P
authors.initials: BP
authors.lastname: Ciszek
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Nackley
mesh_terms: D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology; D058673:Adrenergic beta-3 Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism*; D006930:Hyperalgesia / Q000378:metabolism*; D053583:Interleukin-1beta / Q000187:drug effects / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000378:metabolism
chemical_list: D058672:Adrenergic beta-2 Receptor Antagonists; D058673:Adrenergic beta-3 Receptor Antagonists; D065098:Catechol O-Methyltransferase Inhibitors; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D016207:Cytokines; C000594089:IL1B protein, rat; D053583:Interleukin-1beta; D015850:Interleukin-6; D018343:Receptors, Adrenergic, beta-2; D022702:Receptors, Adrenergic, beta-3; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D002394:Catechol O-Methyltransferase
keywords: Allodynia; Catecholamines; Chemokine (C-C motif) ligand 2 (CCL2); Epinephrine; Hyperalgesia; Inflammation; Interleukin 1 beta (IL-1β); Interleukin 6 (IL-6); Monocyte chemotactic protein 1 (MCP-1); Nitrate; Nitrite; Norepinephrine; Tumor necrosis factor alpha (TNFα)
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