Sex differences in the central regulation of colorectal motility in response to noxious stimuli

Abstract

Distinct sex differences in the prevalence and symptoms of abnormal bowel habits in patients with irritable bowel syndrome (IBS) have been reported. We have elucidated the sex differences in the regulation of colorectal motility via the central nervous system. Noxious stimuli in the colorectum of anesthetized male rats enhance colorectal motility by activating monoaminergic neurons in descending pain inhibitory pathways from the brainstem to the lumbosacral spinal cord. These monoaminergic neurons release serotonin and dopamine into the lumbosacral spinal cord, resulting in the increment of colorectal motility. In female rats, in contrast, noxious stimuli in the colorectum have no effect on colorectal motility. We clarified that GABAergic inhibition in the lumbosacral spinal cord masks the enhancement of colorectal motility induced by monoamines in female animals. Considering that IBS patients often show visceral hypersensitivity and hyperalgesia, our studies suggest that differences in the descending neurons that respond to painful stimuli are involved in various sex differences in abnormal bowel habits.

Introduction

The enteric nervous system, including the myenteric plexus and submucous plexus, senses intraluminal contents and regulates the contraction and relaxation of gastrointestinal smooth muscles (1,2,3). However, the central nervous system also regulates gastrointestinal motility via the modulation of activity of the enteric nervous system. The supraspinal defecation center in the pons and the spinal defecation center in the lumbosacral spinal cord play important roles in the regulation of colorectal motility (4, 5). However, the precise neural pathways regulating colorectal motility remain unclear. Furthermore, how those neural pathways are related to the pathological mechanisms of diarrhea and constipation is unclear. To address these issues, we investigated the regulatory mechanisms of colorectal motility via the central nervous system.

In this review, we summarize the sex differences in the regulatory mechanism of colorectal motility by the central nervous system, with a focus on our recent findings (Fig. 1).

Fig. 1.

A schematic overview of the sexually dimorphic regulation of colorectal motility via the spinal defication center and its relation to sex hormones. In male rats, noxious stimuli activate serotonergic and dopaminergic pathways, which enhance colorectal motility via parasympathetic nerves in the limbosacral spinal cord (male phenotype). In contrast, noxious stimuli have no effect on colorectal motility in female rats due to activation of the GABAergic inhibitory pathway in addition to the serotonergic pathway (female phenotype). Ovariectomy induces a change in the response from the female phenotype to the male phenotype. In contrast, orchiectomy with estradiol treatment switches the male phenotype to the female phenotype.

Sex Differences in Abnormal Bowel Habits and IBS

It is well known that distinct sex differences exist in functional bowel disorders (6, 7) and in patients with irritable bowel syndrome (IBS) (8, 9). For one, the prevalence of IBS is two to four times higher in women than in men. In addition, the symptoms in IBS patients are also sexually dimorphic; female patients often show constipation-type symptoms, whereas male patients often show diarrhea-type symptoms. Sex hormones may be involved in these sex differences, as some symptoms of IBS are altered after menopause in female patients (10).

In the gastrointestinal tract, sex hormones have various effects on enteric neurons (11,12,13) and smooth muscle cells (14,15,16), which may cause sex differences in IBS via changes in peripheral mechanisms. In contrast to peripheral mechanisms, sex differences in central regulation are poorly understood. Given that psychological stress is an important factor influencing IBS (17,18,19), central mechanisms associated with stress may be linked directly to sex differences in IBS. Thus, we focused on sex differences in the central regulation of colorectal motility.

Central Regulation of Colorectal Motility Triggered by Noxious Stimuli

Our previous studies showed that monoamines (dopamine, serotonin and noradrenaline) enhance colorectal motility by acting on the spinal defecation center (20,21,22). These monoamines are known to be neurotransmitters of descending pain inhibitory pathways. These pain inhibitory pathways are activated by noxious signals from peripheral tissues and release monoamines into the spinal cord, resulting in the inhibition of excess transmission of noxious signals (23,24,25). We hypothesized that monoamines released from the descending pain inhibitory pathways also exert a prokinetic effect on the colorectum through the spinal defecation center. In support of this hypothesis, we demonstrated that noxious stimuli induced by injection of capsaicin into the colorectum enhanced colorectal motility. Furthermore, the capsaicin-induced response was abolished by prior injection of antagonists of serotonergic and dopaminergic receptors into the lumbosacral spinal cord (26). These results suggest that descending pain inhibitory pathways regulate both pain signals and colorectal motility via monoaminergic transmission in the lumbosacral spinal cord.

Sex Differences in the Central Regulation of Colorectal Motility

There is accumulating evidence of sex differences in descending pain inhibitory pathways (27, 28). We examined whether or not the central regulation of colorectal motility via descending pain inhibitory pathways also shows sexual dimorphism. Interestingly, capsaicin injection enhanced colorectal motility in male rats but not in female rats. There was no significant sex difference in the expression of TRPV1 channel between the colorectum and dorsal root ganglia. An immunohistochemical analysis with a retrograde tracer showed that dopaminergic and serotonergic neurons projecting from the brain to the lumbosacral spinal cord exist in female rats as well as in male rats. Dopamine and serotonin injection into the spinal cord also enhanced colorectal motility in both sexes. Based on these findings, it appears that dopaminergic and serotonergic pathways to enhance colorectal motility in response to noxious stimuli are preserved even in females. Thus, we assumed the existence of female-specific inhibitory regulation of colorectal motility.

GABA is a representative inhibitory neurotransmitter and is a component of the descending pain inhibitory pathways. To examine whether or not GABAergic inhibition is involved in the lack of a motility response in the colorectum of female rats, a GABA receptor antagonist was intrathecally administered to the lumbosacral spinal cord prior to capsaicin injection. Under this condition, with GABAergic transmission blocked, noxious stimuli induced by capsaicin injection enhanced colorectal motility in female rats as well as in male rats. The capsaicin-induced response in female rats was abolished by intrathecal administration of an inhibitor of the serotonergic receptor but not intrathecal administration of an inhibitor of the dopaminergic receptor, suggesting that the components of the descending pathways that are involved in the response to noxious stimuli are different in males and females (serotonergic and dopaminergic pathways in males and serotonergic and GABAergic pathways in females) (29). Based on these results, we concluded that manifestation of GABAergic transmission contributes to the sexually dimorphic response of colorectal motility.

The GABAergic circuit that regulates colorectal motility has not yet been clarified. However, our previous study provided several candidates for the GABAergic circuit. Electrical stimulation of the raphe nuclei in the medulla oblongata or A11 region in the diencephalon enhanced colorectal motility when an antagonist of the GABA receptor was injected into the lumbosacral spinal cord. GABAergic neurons in the raphe nuclei and/or A11 region may thus be involved in the regulation of colorectal motility. In contrast, GABAergic neurons are also abundantly located in the spinal cord. It is therefore possible that the GABAergic circuit in the spinal cord regulates colorectal motility. Further studies are needed to clarify the GABAergic circuits in the brain and spinal cord.

Contribution of Sex Hormones to the Sex Differences

Sex hormones may contribute to the sex differences in abnormal bowel habits because some symptoms of IBS are altered after menopause in female patients, as mentioned above (10). A recent study showed that central regulation of gastric motility was affected by circulating estrogen levels (30). We therefore examined the involvement of sex hormones in the sexually dimorphic response of colorectal motility.

In male rats, orchiectomy had no effect on the response of colorectal motility induced by capsaicin injection. In contrast, capsaicin injection enhanced colorectal motility in ovariectomized female rats but not in intact female animals. Estradiol treatment in ovariectomized female rats abolished the capsaicin-induced response of colorectal motility as in intact females. Additionally similar to intact female rats, prior injection of a GABA receptor antagonist into the lumbosacral spinal cord enhanced the colorectal motility in response to capsaicin injection in estradiol-treated ovariectomized rats. These findings suggest that estradiol permits the GABAergic inhibitory pathways of colorectal motility to operate in response to noxious signals in female animals. Operation of the GABAergic pathways induced by estradiol treatment was observed even in male rats, although only when orchiectomy had been performed to eliminate the effects of male sex hormones (31). Interestingly, the same regulatory pattern has been found in the control of lordosis, a sexual receptive behavior in rodents. Estradiol treatment facilitates the induction of lordosis in female animals and even in male animals, albeit only when those male have been orchiectomized (32,33,34). This similarity between the regulatory patterns of colorectal motility and the regulatory patterns of sexual behavior suggests that neural circuits regulating colorectal motility overlap with neural circuits regulating sexual behavior. Clinical studies have shown associations of IBS with sexual dysfunction, such as erectile dysfunction (17, 35, 36). One possible reason for this is that sex hormones affect both neural circuits for colorectal motility and sexual behavior, which causes defecation dysfunction in IBS and sexual dysfunction simultaneously.

Conclusion

We found that there are sex differences in the central regulation of colorectal motility and that sex hormones contribute to this sexual dimorphism. A further investigation of the action sites of sex hormones in the central nervous system will reveal the precise neural circuits for control of colorectal motility and their sex differences. Elucidation of the neural circuits may provide important information to aid in the diagnosis of IBS and/or identification of therapeutic targets for IBS. Elucidation of the sex differences in the central regulatory mechanisms of colorectal motility in addition to peripheral mechanisms will lead to an integrative understanding of sex differences in abnormal bowel habits and IBS.

Conflict of Interest

The authors declare no conflicts of interest.