title: Persistent Catechol-O-methyltransferase-dependent Pain Is Initiated by Peripheral β-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 β-adrenergic receptor (βAR) activation. The contribution of distinct βAR 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 βARs 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 βAR 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 βAR antagonist propranolol, the β2AR antagonist ICI-118,511, or the β3AR 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 βAR antagonists may benefit chronic pain patients.
authors.affiliation: From the Dental Research Department, Center for Pain Research and Innovation, University of North Carolina, Chapel Hill, North Carolina. Current affiliation: Center for Translational Pain Medicine, Department of Anesthesiology, Duke University School of Medicine, Durham, North Carolina (A.G.N.).
authors.forename: Brittney P
authors.initials: BP
authors.lastname: Ciszek
authors.forename: Sandra C
authors.initials: SC
authors.lastname: O'Buckley
authors.forename: Andrea G
authors.initials: AG
authors.lastname: Nackley
mesh_terms: D000315:Adrenalectomy; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002394:Catechol O-Methyltransferase / Q000378:metabolism*; D065098:Catechol O-Methyltransferase Inhibitors / Q000494:pharmacology; D002396:Catechols / Q000494:pharmacology; D005260:Female; D006358:Hot Temperature; D007278:Injections, Spinal; D008297:Male; D010146:Pain / Q000201:enzymology*; D010147:Pain Measurement / Q000187:drug effects; D017933:Peripheral Nervous System / Q000187:drug effects*; D010812:Physical Stimulation; D011412:Propanolamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*
chemical_list: C097869:3-(2-ethylphenoxy)-1-(1,2,3,4-tetrahydronaphth-1-ylamino)-2-propanol oxalate; D000319:Adrenergic beta-Antagonists; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; C026777:ICI 118551; D002394:Catechol O-Methyltransferase; C057726:OR486