The hormone melatonin is primarily produced by the pineal gland and released into blood circulation during the dark period of the environmental light/dark cycle (Moore, 1996). Two mammalian subtypes of G protein-coupled melatonin receptor, termed MT1 and MT2 (formerly termed Mel1a and Mel1b), have been cloned and characterized (Reppert et al., 1994, 1995). Both receptors primarily couple to Gi protein and also couple to Gq protein depending on cellular type (Nikolaev). MT1 and MT2 receptors are expressed in various areas of central nervous system (CNS) and peripheral tissues (DubocovichMarkowska; Slominski et al., 2012; von Gall et al., 2002). Melatonin receptors in the CNS are involved in the regulation of sleep and circadian rhythm (Dubocovich). Melatonin and its synthetic analogs ramelteon and tasimelteon are therefore widely used for the treatment of sleep disorders, including insomnia and circadian sleep disorders (Kim and Yang, 2022).

Nocturia is defined as waking to pass urine during the main sleep period. The first nocturia episode must be preceded by sleep. Subsequent nocturia episodes must be followed by the intention of getting back to sleep (Hashim). A variety of factors can cause nocturia, including excessive production of urine at night (nocturnal polyuria) and decreased functional bladder capacity (Kim and Chung, 2022). Desmopressin is the only drug approved for the treatment of nocturia, specifically nocturnal polyuria only (Przydacz). Sleep disorders are also proposed to cause nocturia, and pharmacotherapies for sleep disorders are expected to improve nocturia symptoms (Kim and Chung, 2022).

Several clinical trials have suggested that melatonin has therapeutic effects in nocturia patients (Batla; Drake et al., 2004; Leerasiri et al., 2023). Melatonin is considered to alleviate nocturia symptoms mainly by improving sleep disturbance. In addition, animal studies have suggested that melatonin has other beneficial actions on nocturia symptoms. Examples include inhibition of bladder contraction and increased bladder capacity in rats via the modulation of CNS γ-aminobutyric acid neurons (Matsuta) and a direct effect on the peripheral lower urinary tract to decrease the contraction response of bladder smooth muscle by a receptor-independent mechanism (Han et al., 2012). Melatonin is thought to exert its effects on lower urinary tract function through a variety of mechanisms. However, there is little information regarding the expression and functional role of melatonin receptors in bladder and urethral tissues.

Here, we assessed expression levels of melatonin receptor mRNA in bladder and urethra. Further, to elucidate the role of melatonin receptors in the lower urinary tract, we investigated the influence of melatonin receptor activation on tension of isolated female rat urethra and bladder strips using melatonin receptor agonists and an antagonist. We then examined the mechanism underlying the urethral response to melatonin receptor stimulation in isolated urethral strip experiments. Finally, we investigated the in vivo effect of melatonin receptor agonists on urethral muscle by measuring urethral pressure in anesthetized female rats.