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.

Systems Pharmacogenomics – Gene, Disease, Drug and Placebo Interactions: A Case Study in COMT

“…In several studies, postsurgical cancer patients who were met-allele homozygotes had a lower pain threshold and higher levels of fatigue [41]. Consistent with these profiles, in wild-type mice, sustained delivery of the COMT inhibitor OR486 increased sensitivity to mechanically induced pain [63]. COMT knockout mice have enhanced sensitivity to thermal pain, and transgenic mice that overexpress COMT are more resistant to thermal pain [60].…”

β2- and β3-adrenergic receptors drive COMT-dependent pain by increasing production of nitric oxide and cytokines

“…Another recent study by our group shows that adrenalectomized rats, lacking peripheral epinephrine, fail to develop increased mechanical and thermal pain sensitivity following sustained COMT inhibition, thus providing further evidence for a peripheral contribution of adrenergic systems to COMT-dependent pain. [10]. Additional work is required to determine the relative contributions of peripheral, spinal, and supraspinal β 2 - and β 3 ARs to COMT-dependent pain.…”

Risk factors and prognosis of pain events during mechanical ventilation: a retrospective study

“…The correlation between inotropic support and disuse of fentanyl in this study was low ( r = 0.16). An experimental animal study revealed that a higher blood catecholamine concentration is associated with increased pain sensitivity via the activation of β-adrenergic receptors in the peripheral sensory nerves [ 18 ].…”