Serotonin enhances urinary bladder nociceptive processing via a 5-HT3 receptor mechanism

Abstract

Serotonin from the descending pain modulatory pathway is critical to nociceptive processing. Its effects on pain modulation may either be inhibitory or facilitatory, depending on the type of pain and which receptors are involved. Little is known about the role of serotonergic systems in bladder nociceptive processing. These studies examined the effect of systemic administration of the serotonin precursor, 5-hydroxytryptophan (5-HTP), on normal bladder and somatic sensation in rats. ELISA was used to quantify peripheral and central changes in serotonin and its major metabolite following 5-HTP administration, and the potential role of the 5-HT3 receptor on changes in bladder sensation elicited by 5-HTP was investigated. 5-HTP produced bladder hypersensitivity and somatic analgesia. The pro-nociceptive effect of 5-HTP was attenuated by intrathecal, but not systemic, ondansetron. Peripheral increases in serotonin, its metabolism and rate of turnover were detectable within 30 min of 5-HTP administration. Significant enhancement of serotonin metabolism was observed centrally. These findings suggest that 5-HTP increases serotonin, which may then affect descending facilitatory systems to produce bladder hypersensitivity via activation of spinal 5-HT3 receptors.

Dynamic Expression of Serotonin Receptor 5-HT3A in Developing Sensory Innervation of the Lower Urinary Tract

“…Pharmacological activation of 5-HT3A at spinal and supraspinal terminals resulted in inhibited sensory processing and a decreased micturition threshold volume (Espey et al, 1998). Complementary experiments showed that intrathecal administration of a 5-HT3A antagonist led to bladder nociceptive hypersensitivity (Hall et al, 2015), further supporting a critical role for 5-HT3A in sensory mediation of bladder filling and voiding. Future studies will need to focus on elucidating the specific functional impact of this receptor on bladder contractility and the consequences of its absence during nervous system development.…”

“…Given the known significance of 5-HT3A signaling in visceral nociception and neural control of bladder function (Zeitz et al, 2002; Bhattacharya et al, 2004; Faerber et al, 2007; Hall et al, 2015), we next sought to determine the proportion of 5-HT3A+ DRG neurons that contribute to bladder sensory innervation in adult mice. To do this, we conducted retrograde tracing of bladder innervation in adult male transgenic mice by injecting Fast Blue (FB) dye into the detrusor and quantified proportions of Htr3a -EGFP+ neurons whose soma were labeled with FB (Table 3 and Figure 7D).…”

“…One such receptor, 5-HT3A (encoded by Htr3a in mice), is a ligand-gated ion channel with previously established roles in potentiating pain (Zeitz et al, 2002; Hall et al, 2015). Despite its known expression in fetal neural crest derivatives (Tecott et al, 1993, 1995), comprehensive temporal profiling of 5-HT3A in developing sensory neuron populations has not been pursued.…”

“…Differentiation of DRG neurons and acquisition of sensory subtype-specific markers has been reported around 14.5 dpc (Marmigerè and Ernfors, 2007; Bachy et al, 2011; Zou et al, 2012). Despite evidence that points to an effect of 5-HT3A on bladder function (Espey et al, 1998; Bhattacharya et al, 2004; Hall et al, 2015), no prior studies have assessed the expression of this receptor in DRG during the developmental stages when the LUT is being innervated. To date, Htr3a gene expression in DRG has only been characterized via in situ hybridization at a single developmental time point (Tecott et al, 1993; Diez-Roux et al, 2011).…”

Anti-nociceptive effects of Paecilomyces hepiali via multiple pathways in mouse models

“…5-HT is widely accepted as a key neurotransmitter in the pathophysiology of migraines, and low levels of 5-HT are found in patients who suffer from chronic daily headaches (le Grand et al, 2011). System administration with the serotonin precursor 5-hydroxytryptophan significantly increases serotonin and provides somatic analgesia (Hall et al, 2015). Moreover, the non-selective serotonin antagonist metergoline antagonizes mirtazapine-induced antinociceptive effects (Schreiber et al, 2002).…”