(312) Peripherally located β2- and β3-adrenergic receptors contribute to the development of COMT-dependent pain in rats, but not the maintenance of pain in COMT-/- mice

Abstract

Genetic and pharmacologic alterations resulting in reduced catechol-O-methyltransferase (COMT) activity are associated with increased pain sensitivity and onset of chronic pain conditions. COMT-dependent pain is mediated via β2 and β3-adrenergic receptors (ARs), which are located in various regions where they could potentially drive pain transmission. In order to determine the site of action whereby βARs drive COMT-dependent pain, the present study measured evoked pain behaviors in rats receiving βAR antagonists peripherally, spinally or supraspinally alongside administration of COMT inhibitor OR486. Osmotic pumps were utilized to achieve sustained subcutaneous (s.c.), intrathecal and intracerebroventricular delivery of βAR antagonists, and sustained s.c. delivery of OR486, over a 2-week period. Responses to mechanical and thermal stimuli were assessed prior to and following pump implantation. Rats receiving sustained OR486 demonstrated decreased paw withdrawal thresholds and increased paw withdrawal frequency in response to mechanical stimuli and decreased paw withdrawal latency in response to thermal heat. Peripheral, but not spinal or supraspinal, administration of non-selective βAR antagonist propranolol, β2AR antagonist ICI-118,511 or β3AR antagonist SR59230A blocked the development of OR486-induced pain. Next, we examined the ability of peripherally administered β2- and β3AR antagonists to reverse pain in COMT-/- mice. Osmotic pumps were utilized to achieve sustained s.c. delivery of ICI-118,511 together with SR59230A over a 2-week period. Responses to mechanical and thermal stimuli were assessed prior to and following pump implantation. Peripheral delivery of βAR antagonists failed to block endogenous mechanical and thermal pain in COMT-/- mice. In summary, peripherally located β2- and β3-adrenergic receptors contribute to the development of COMT-dependent pain in rats, but not the maintenance of pain in COMT-/- mice. These results suggest that the use of peripherally-acting βAR antagonists may be beneficial in acute clinical and/or surgical settings to prevent the development of chronic pain among susceptible individuals. Funding: NIH/NINDS R01-NS072205 and P01-NS045685.