Catechol-O-methyltransferase inhibition increases pain sensitivity through activation of both beta2- and beta3-adrenergic receptors

Abstract

Catechol-O-methyltransferase (COMT), an enzyme that metabolizes catecholamines, has recently been implicated in the modulation of pain. Our group demonstrated that human genetic variants of COMT are predictive for the development of Temporomandibular Joint Disorder (TMJD) and are associated with heightened experimental pain sensitivity [Diatchenko, L, Slade, GD, Nackley, AG, Bhalang, K, Sigurdsson, A, Belfer, I, et al., Genetic basis for individual variations in pain perception and the development of a chronic pain condition, Hum Mol Genet 2005;14:135-43.]. Variants associated with heightened pain sensitivity produce lower COMT activity. Here we report the mechanisms underlying COMT-dependent pain sensitivity. To characterize the means whereby elevated catecholamine levels, resulting from reduced COMT activity, modulate heightened pain sensitivity, we administered a COMT inhibitor to rats and measured behavioral responsiveness to mechanical and thermal stimuli. We show that depressed COMT activity results in enhanced mechanical and thermal pain sensitivity. This phenomenon is completely blocked by the nonselective beta-adrenergic antagonist propranolol or by the combined administration of selective beta(2)- and beta(3)-adrenergic antagonists, while administration of beta(1)-adrenergic, alpha-adrenergic, or dopaminergic receptor antagonists fail to alter COMT-dependent pain sensitivity. These data provide the first direct evidence that low COMT activity leads to increased pain sensitivity via a beta(2/3)-adrenergic mechanism. These findings are of considerable clinical importance, suggesting that pain conditions resulting from low COMT activity and/or elevated catecholamine levels can be treated with pharmacological agents that block both beta(2)- and beta(3)-adrenergic receptors.

Figures

Fig. I

COMT inhibition produces tactile allodynia, mechanical hyperalgesia, and thermal hyperalgesia. Administration of the COMT inhibitors OR486 (30 mg/kg) or RO41-0960 (30 mg/kg) (A) decreased paw withdrawal threshold to mechanical stimuli (4.04 ± 0.32 g and 8.01 ± 0.56 g for animals receiving OR486 and RO41-0960, respectively, relative to controls with a paw withdrawal threshold of 20.76 ± 0.37 g), (B) increased paw withdrawal frequency to repeated presentation of a 25 g monofilament (46.56 ± 2.82 % and 22.81 ± 2.33 % for animals receiving OR486 and RO41-0960, respectively, relative to controls with a paw withdrawal frequency of 7.97 ± 1.10 %), and (C) decreased paw withdrawal latency to thermal stimuli relative to vehicle (5.09 ± 0.24 s and 6.56 ± 0.25 s for animals receiving OR486 and RO41-0960, respectively, compared to controls with a paw withdrawal latency of 7.92 ± 0.25 s). Animals receiving OR486 (30 mg/kg) + saline or vehicle + carrageenan (3%) produced a similar degree of (D) tactile allodynia and (E) mechanical hyperalgesia relative to those receiving vehicle + saline. Furthermore, administration of OR486 + carrageenan produced an additive effect on behavioral responsiveness to mechanical stimuli relative to those receiving either vehicle + carrageenan or OR486 + saline (panel D and E insets). (F) Animals receiving OR486 + saline, vehicle + carrageenan, or OR486 + carrageenan also produced a similar degree of thermal hyperalgesia relative to those receiving vehicle + saline. N = 8 per group. Data are Mean ± SEM. ***P < 0.001, **P < 0.01, *P < 0.05 different from vehicle (A–C) or vehicle + saline (D–F). #P < 0.05 different from vehicle + carrageenan and OR486 + saline.

Fig. II

Administration of the nonselective βAR antagonist propranolol completely blocks OR486-induced pain sensitivity. Administration of propranolol (3 mg/kg) prior to OR486 (30 mg/kg) normalized (A) paw withdrawal threshold to mechanical stimuli, (B) paw withdrawal frequency to a noxious punctate stimulus, and (C) paw withdrawal latency to radiant heat relative to animals receiving the α-adrenergic antagonist phentolamine (3 mg/kg), D1-like dopamine antagonist SCH23390 (0.2 mg/kg), D2-like dopamine antagonist spiperone (0.2 mg/kg), or vehicle prior to OR486. Administration of phentolamine, propranolol, SCH23390, or spiperone 10 min prior to i.p. administration of vehicle failed to affect (D) paw withdrawal threshold to mechanical stimuli, (E) paw withdrawal frequency to a noxious punctate stimulus, or (F) paw withdrawal latency to radiant heat relative to vehicle. N = 8 per group. Data are Mean ± SEM. ***P < 0.001, **P < 0.01, *P < 0.05 different from vehicle + OR486.

Fig. III

Administration of selective antagonists for β2- or β3ARs reduces OR486-induced pain sensitivity. Administration of the middle (0.5 mg/kg) or high (5.0 mg/kg) dose of the β2 antagonist ICI118,551 prior to OR486 (30 mg/kg) (A) increased paw withdrawal threshold and (B) decreased paw withdrawal frequency to a noxious punctate stimulus relative to animals receiving vehicle or the low (0.05 mg/kg) dose of ICI118,551. (C) Administration of the high dose of ICI118,551 also increased paw withdrawal latency to radiant heat relative to animals receiving vehicle prior to OR486. Administration of the middle (5 mg/kg) or high (50 mg/kg) dose of the β3 antagonist SR59230A prior to OR486 (30 mg/kg) (D) increased paw withdrawal threshold to mechanical stimuli, (E) decreased paw withdrawal frequency to a noxious punctate stimulus, and (F) increased paw withdrawal latency to thermal stimuli relative to animals receiving vehicle. (G–I) Administration of the β1AR antagonist betaxolol (0.1, 1.0, or 10 mg/kg) prior to OR486 failed to alter pain sensitivity. Administration of ICI118,551, SR59230A, or betaxolol 10 min prior to i.p. administration of vehicle failed to affect (J) paw withdrawal threshold to mechanical stimuli, (K) paw withdrawal frequency to a noxious punctate stimulus, or (L) paw withdrawal latency to radiant heat relative to vehicle. N = 8 per group. Data are expressed as Mean ± SEM. ***P < 0.001, **P < 0.01, *P < 0.05 different from vehicle + vehicle. +++P < 0.001, ++P < 0.01, +P < 0.05 different from vehicle + OR486.

Fig. IV

Coadministration of selective antagonists for β2- and β3ARs completely blocks OR486-induced pain sensitivity. Concurrent administration of ICI118,551 (0.5 mg/kg) and SR59230A (5.0 mg/kg) prior to OR486 (30 mg/kg) completely normalized (A) paw withdrawal threshold to mechanical stimuli, (B) paw withdrawal frequency to a noxious punctate stimulus, and (C) paw withdrawal latency to radiant heat. N = 8 per group. Data are expressed as Mean ± SEM. ***P < 0.001, **P < 0.01 different from vehicle + OR486.