Adrenergic β2-receptor Mediates Itch Hypersensitivity Following Heterotypic Chronic Stress In Rats

Background & Aims: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. First of all, the present study aimed to elucidate that heterotypic chronic intermittent stress(HIS) in rats,can increase itching behavior. Furthermore,we also elucidate the role of adrenergic signaling in itch hypersensitivity following heterotypic chronic intermittent stress(HIS) in rats.Methods:Itch sensitization was induced in 6-8 week old male SD rats by 9 day stress protocol comprised of 3 randomly arranged stressors: cold stressor forced swimming stressor and water avoidance stressor. By drug intervention, to determine α, β receptor in a receptor involved in the pathological process in rats with stress-induced pruritus. Using Western Blotting detected in the control group of rats and skin HIS group β2-adrenergic receptors,and TNF-α expression of inflammatory factors in skin tissue. Uising QPCR detected different groups expression inflammatory factors of TNF-α, IL-1β, IL-6, NGF.Result: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 both5-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 theβ2-adrenoceptor antagonist butoxamine, but not on treatment with anα-adrenoceptor antagonist phentolamine and aβ1-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. Theβ-blockers propranolol and butoxamine abolished the upregulation ofproinflammatory factors.Conclusion:Theβ2-adrenoceptor agonist terbutaline was sufficient to enhance the skin expression of TNF-αand IL-1βand to increase 5-HT-induced scratching in naive rats. Pretreatment with TNF-αcould increase 5-HT-induced scratching. Together, these results demonstrate thatβ2-adrenoceptors mediate itch hypersensitivity following chronic stress by inducing proinflammatory factors, such as TNF-α, in the skin.