Dual Effect of Catecholamines and Corticosterone Crosstalk on Pineal Gland Melatonin Synthesis

Abstract

Background/Aim: The nocturnal production of melatonin by the pineal gland is triggered by sympathetic activation of adrenoceptors and may be modulated by immunological signals. The effect of glucocorticoids on nocturnal melatonin synthesis is controversial; both stimulatory and inhibitory effects have been reported. During pathophysiological processes, an increased sympathetic tonus could result in different patterns of adrenoceptor activation in the pineal gland. Therefore, in this investigation, we evaluated whether the pattern of adrenergic stimulation of the pineal gland drives the direction of the glucocorticoid effect on melatonin production. Methods: The corticosterone effect on the pineal hormonal production induced by β-adrenoceptor or β+α₁-adrenoceptor activation was evaluated in cultured glands. We also investigated whether the in vivo lipopolysaccharide (LPS)-induced inhibition of melatonin is dependent on the interaction of glucocorticoids and the α₁-adrenoceptor in adrenalectomized animals and on the in vivo blockade of glucocorticoid receptors (GRs) or the α₁-adrenoceptor. Results: Corticosterone potentiated β-adrenoceptor-induced pineal melatonin synthesis, whilst corticosterone-dependent inhibition was observed when melatonin production was induced by β+α₁-adrenoceptors agonists. The inhibitory effect of corticosterone is mediated by GR, as it was abolished in the presence of a GR antagonist. Moreover, LPS-induced reduction in melatonin nocturnal plasma content was reversed by adrenalectomy and by antagonizing GR or α₁-adrenoceptors. Conclusions: The dual effect of corticosterone on pineal melatonin synthesis is determined by the activation pattern of adrenoceptors (β or β+α₁) in the gland during GR activation, suggesting that increased activation of the sympathetic system and the hypothalamic-pituitary-adrenal axis are necessary for the control of melatonin production during defense responses.

β-Adrenoceptors Trigger Melatonin Synthesis in Phagocytes

“…Indeed, sympathetic stimulation is essential for triggering the recovery phase of an immune response [52,53] in lymph nodes [54], bone marrow cells [55], and gut macrophages [56]. Melatonin produced on demand by immune cells [1,31] could represent a new player in the defense response not only directed to PAMPs and DAMPs but also mediated by activation of the sympathetic nervous system [57]. Taken together, our data provide further support to the new concept of endogenously and extra-pineal produced melatonin as an integral player in the function of phagocytes in situations of infection and/or sympathetic activation.…”

Melatoninergic System in Parkinson’s Disease: From Neuroprotection to the Management of Motor and Nonmotor Symptoms

“…Melatonin synthesized by phagocytes acts in a paracrine manner favouring the phagocytosis of bacteria, fungi, parasites, and cellular debris [17, 41, 45, 46]. The synthesis of melatonin by the pineal gland is restored before the end of the acute inflammatory response, due to the inhibition of NF- κ B by glucocorticoids released from the adrenal gland [29, 47, 48]. …”

Daily corticosterone rhythm modulates pineal function through NFκB-related gene transcriptional program

“…The interplay between the two hormones has been evaluated in stressful conditions or in models of infection 8–11 . The anti-inflammatory effect of glucocorticoids mediated by activation of transcription programs is triggered by the nuclear translocation of the glucocorticoid receptor (GR) 12 .…”

“…As for melatonin, its activity reduces oxidative stress and inhibits the nuclear translocation of the nuclear factor kappa B (NFκB), a pivotal transcription factor for inflammatory responses 13–15 . In stressful conditions, signalized by simultaneous activation of both α and β adrenoceptors, corticosterone reduces the synthesis of melatonin in the pineal gland 11 . On the other hand, this synthesis is stimulated by low stressful conditions when only β-adrenoceptors are triggered 8, 11 .…”

“…In stressful conditions, signalized by simultaneous activation of both α and β adrenoceptors, corticosterone reduces the synthesis of melatonin in the pineal gland 11 . On the other hand, this synthesis is stimulated by low stressful conditions when only β-adrenoceptors are triggered 8, 11 . Moreover, in healthy rats, trans-pineal perfusion of corticosterone, both at the light or dark phase leads to a significant increase in nocturnal melatonin output, with no change in daytime levels 9 , suggesting a putative interaction between the daily rhythms of corticosterone and melatonin.…”