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 β2- and β3-adrenergic receptors (β2- and β3ARs) through the release of the pro-inflammatory
cytokines tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and
interleukin-6 (IL-6). Here, we first sought to investigate the role of β2- and β3ARs 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 β2AR antagonist ICI118551 and β3AR antagonist
SR59230A were co-administrated subcutaneously with
OR486 or vehicle either on day 0 or day 7. The TNFα 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 TNFα, IL-1β, 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 β2- and β3ARs 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.