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Persistent Catechol-O-methyltransferase-dependent Pain Is Initiated by Peripheral ?-Adrenergic Receptors.

ABSTRACT: BACKGROUND:Patients with chronic pain disorders exhibit increased levels of catecholamines alongside diminished activity of catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines. The authors found that acute pharmacologic inhibition of COMT in rodents produces hypersensitivity to mechanical and thermal stimuli via ?-adrenergic receptor (?AR) activation. The contribution of distinct ?AR populations to the development of persistent pain linked to abnormalities in catecholamine signaling requires further investigation. METHODS:Here, the authors sought to determine the contribution of peripheral, spinal, and supraspinal ?ARs to persistent COMT-dependent pain. They implanted osmotic pumps to deliver the COMT inhibitor OR486 (Tocris, USA) for 2 weeks. Behavioral responses to mechanical and thermal stimuli were evaluated before and every other day after pump implantation. The site of action was evaluated in adrenalectomized rats receiving sustained OR486 or in intact rats receiving sustained ?AR antagonists peripherally, spinally, or supraspinally alongside OR486. RESULTS:The authors found that male (N = 6) and female (N = 6) rats receiving sustained OR486 exhibited decreased paw withdrawal thresholds (control 5.74 ± 0.24 vs. OR486 1.54 ± 0.08, mean ± SEM) and increased paw withdrawal frequency to mechanical stimuli (control 4.80 ± 0.22 vs. OR486 8.10 ± 0.13) and decreased paw withdrawal latency to thermal heat (control 9.69 ± 0.23 vs. OR486 5.91 ± 0.11). In contrast, adrenalectomized rats (N = 12) failed to develop OR486-induced hypersensitivity. Furthermore, peripheral (N = 9), but not spinal (N = 4) or supraspinal (N = 4), administration of the nonselective ?AR antagonist propranolol, the ?2AR antagonist ICI-118,511, or the ?3AR antagonist SR59230A blocked the development of OR486-induced hypersensitivity. CONCLUSIONS:Peripheral adrenergic input is necessary for the development of persistent COMT-dependent pain, and peripherally-acting ?AR antagonists may benefit chronic pain patients.

SUBMITTER: Ciszek BP

PROVIDER: S-EPMC5015695 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Project description:Functional pain syndromes, such as fibromyalgia and temporomandibular disorder, are associated with enhanced catecholamine tone and decreased levels of catechol-O-methyltransferase (COMT; an enzyme that metabolizes catecholamines). Consistent with clinical syndromes, our lab has shown that sustained 14-day delivery of the COMT inhibitor OR486 in rodents results in pain at multiple body sites and pain-related volitional behaviors. The onset of COMT-dependent functional pain is mediated by peripheral ?2- and ?3-adrenergic receptors (?2- and ?3ARs) through the release of the pro-inflammatory cytokines tumor necrosis factor ? (TNF?), interleukin-1? (IL-1?), and interleukin-6 (IL-6). Here, we first sought to investigate the role of ?2- and ?3ARs and downstream mediators in the maintenance of persistent functional pain. We then aimed to characterize the resulting persistent inflammation in neural tissues (neuroinflammation), characterized by activated glial cells and phosphorylation of the mitogen-activated protein kinases (MAPKs) p38 and extracellular signal-regulated kinase (ERK). Separate groups of rats were implanted with subcutaneous osmotic mini-pumps to deliver OR486 (15?mg/kg/day) or vehicle for 14?days. The ?2AR antagonist ICI118551 and ?3AR antagonist SR59230A were co-administrated subcutaneously with OR486 or vehicle either on day 0 or day 7. The TNF? inhibitor Etanercept, the p38 inhibitor SB203580, or the ERK inhibitor U0126 were delivered intrathecally following OR486 cessation on day 14. Behavioral responses, pro-inflammatory cytokine levels, glial cell activation, and MAPK phosphorylation were measured over the course of 35?days. Our results demonstrate that systemic delivery of OR486 leads to mechanical hypersensitivity that persists for at least 3?weeks after OR486 cessation. Corresponding increases in spinal TNF?, IL-1?, and IL-6 levels, microglia and astrocyte activation, and neuronal p38 and ERK phosphorylation were observed on days 14-35. Persistent functional pain was alleviated by systemic delivery of ICI118551 and SR59230A beginning on day 0, but not day 7, and by spinal delivery of Etanercept or SB203580 beginning on day 14. These results suggest that peripheral ?2- and ?3ARs drive persistent COMT-dependent functional pain via increased activation of immune cells and production of pro-inflammatory cytokines, which promote neuroinflammation and nociceptor activation. Thus, therapies that resolve neuroinflammation may prove useful in the management of functional pain syndromes.

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Persistent Catechol-O-methyltransferase-dependent Pain Is Initiated by Peripheral ?-Adrenergic Receptors.

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