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Sustained stimulation of β2- and β3-adrenergic receptors leads to persistent functional pain and neuroinflammation.

Publication ,  Journal Article
Zhang, X; Hartung, JE; Bortsov, AV; Kim, S; O'Buckley, SC; Kozlowski, J; Nackley, AG
Published in: Brain Behav Immun
October 2018

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.

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Published In

Brain Behav Immun

DOI

EISSN

1090-2139

Publication Date

October 2018

Volume

73

Start / End Page

520 / 532

Location

Netherlands

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Tumor Necrosis Factor-alpha
  • Temporomandibular Joint Disorders
  • Spinal Cord
  • Receptors, Adrenergic, beta-3
  • Receptors, Adrenergic, beta-2
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Pyridines
 

Citation

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ICMJE
MLA
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Zhang, X., Hartung, J. E., Bortsov, A. V., Kim, S., O’Buckley, S. C., Kozlowski, J., & Nackley, A. G. (2018). Sustained stimulation of β2- and β3-adrenergic receptors leads to persistent functional pain and neuroinflammation. Brain Behav Immun, 73, 520–532. https://doi.org/10.1016/j.bbi.2018.06.017
Zhang, Xin, Jane E. Hartung, Andrey V. Bortsov, Seungtae Kim, Sandra C. O’Buckley, Julia Kozlowski, and Andrea G. Nackley. “Sustained stimulation of β2- and β3-adrenergic receptors leads to persistent functional pain and neuroinflammation.Brain Behav Immun 73 (October 2018): 520–32. https://doi.org/10.1016/j.bbi.2018.06.017.
Zhang X, Hartung JE, Bortsov AV, Kim S, O’Buckley SC, Kozlowski J, et al. Sustained stimulation of β2- and β3-adrenergic receptors leads to persistent functional pain and neuroinflammation. Brain Behav Immun. 2018 Oct;73:520–32.
Zhang, Xin, et al. “Sustained stimulation of β2- and β3-adrenergic receptors leads to persistent functional pain and neuroinflammation.Brain Behav Immun, vol. 73, Oct. 2018, pp. 520–32. Pubmed, doi:10.1016/j.bbi.2018.06.017.
Zhang X, Hartung JE, Bortsov AV, Kim S, O’Buckley SC, Kozlowski J, Nackley AG. Sustained stimulation of β2- and β3-adrenergic receptors leads to persistent functional pain and neuroinflammation. Brain Behav Immun. 2018 Oct;73:520–532.
Journal cover image

Published In

Brain Behav Immun

DOI

EISSN

1090-2139

Publication Date

October 2018

Volume

73

Start / End Page

520 / 532

Location

Netherlands

Related Subject Headings

  • p38 Mitogen-Activated Protein Kinases
  • Tumor Necrosis Factor-alpha
  • Temporomandibular Joint Disorders
  • Spinal Cord
  • Receptors, Adrenergic, beta-3
  • Receptors, Adrenergic, beta-2
  • Receptors, Adrenergic, beta
  • Rats, Sprague-Dawley
  • Rats
  • Pyridines