Adrenergic β2-receptor mediates itch hypersensitivity following heterotypic chronic stress in rats

Abstract

Chronic stress is widely considered to trigger or enhance itch, especially for pruritic dermatitis. However, the molecular mechanisms linking chronic stress and itch are still unknown. The present study aimed to elucidate the role of adrenergic signaling in itch hypersensitivity following heterotypic chronic intermittent stress (HIS) in rats. HIS significantly increased hindlimb scratching, but not forepaw swiping, induced by intradermal injection of 5-hydroxytryptamine (5-HT) in the rat cheek. Coadministration of stress mediators such as norepinephrine or epinephrine dose-dependently increased both 5-HT-induced hindlimb scratching and 5-HT-induced forepaw swiping. HIS-induced itch hypersensitivity was attenuated by blockade of sympathetic signaling through guanethidine treatment, and systemic administration of the β-adrenoceptor antagonist propranolol and the β2-adrenoceptor antagonist butoxamine, but not on treatment with an α-adrenoceptor antagonist phentolamine and a β1-adrenoceptor antagonist atenolol. Moreover, HIS selectively increased the expression of β2-adrenoceptors and proinflammatory factors [tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and nerve growth factor (NGF)] in rat skin. The β-blockers propranolol and butoxamine abolished the upregulation of proinflammatory factors. The β2-adrenoceptor agonist terbutaline was sufficient to enhance the skin expression of TNF-α and IL-1β and to increase 5-HT-induced scratching in naive rats. Pretreatment with TNF-α could increase 5-HT-induced scratching. Together, these results demonstrate that β2-adrenoceptors mediate itch hypersensitivity following chronic stress by inducing proinflammatory factors, such as TNF-α, in the skin.

Peripheral and spinal 5-HT receptors participate in cholestatic itch and antinociception induced by bile duct ligation in rats

“…As described previously646566, we intradermally injected chemicals into the cheek of rats. Rats were shaved on cheeks (approx.…”

“…As previously described4366, tail immersion test was employed to determine heat pain sensitivity in rats. Briefly, the terminal 3 cm of a rat’s tail was immersed in hot water bath at 52 °C and the latency of tail flick was recorded with a cutoff time of 15 seconds to avoid tissue damage.…”

“…To test mechanical hypersensitivity, we determined the mechanical sensitivity of hind paws by using series of von Frey filaments (4 g, 15 g, and 26 g) as previous report66. Rats were placed on a metal mesh floor and von Frey filaments were applied from underneath the floor.…”

The role of β‐blockers in dermatological treatment: a review

“…81 Atenolol was reported to be effective in treating IAP. 83 Propranolol's therapeutic effect in treating IAP may also be explained by its role as an antagonist for certain serotonin receptors. 82 Recently, researchers discovered that injection of 5-hydroxytryptamine (5-HT) can induce scratching in na€ ıve rats.…”

The behavioral study on the interactive aggravation between pruritus and depression

“…Peng et al. () found that chronic stress significantly enhances the scratching number when administrating 5‐HT into cheek skin in rats, and β 2 ‐adrenoceptors may mediate itch hypersensitivity via upregulating proinflammatory factors, such as TNF‐α in the skin. All the studies mentioned previously concentrated on the facilitative effects of chronic stress (depression) on itch hypersensitivity instead of the effects of chronic itch on depression.…”