Chronic constipation: improved understanding offers a new therapeutic approach (2016)

In this issue of The Journal of Physiology, Naitou et al. (2016) show that the dopaminergic innervation of the spinal cord, derived from descending pathways originating in the brain, can release dopamine into the lumbosacral defecation centre of the spinal cord (L6–S1 region), where it acts primarily at dopamine D2-like receptors to increase sacral (pelvic) parasympathetic nerve firing and thereby stimulate colorectal propulsive motility. This excitatory action contrasts with an ability of dopamine to inhibit colonic movements when applied directly to the rodent colon (e.g. Walker et al. 2000; Zhang et al. 2012) and to inhibit gastric emptying and oro-caecal transit time in human volunteers when given intravenously (Levein et al. 1999). However, it does have some similarity with the reported ability of intravenously administered dopamine to increase colonic and rectal movements in healthy volunteers (Lanfranchi et al. 1978; Wiley & Owyang, 1987). Together, these data suggest a potentially important role for this monoamine – released within the spinal cord or peripherally – in the control of lower bowel functions. They provide a theoretical pathway by which chronic constipation can develop in patients with Parkinson's disease, where there is degeneration of the brain areas supplying the dopaminergic innervation of the spinal cord. Thus, a reduction in dopaminergic input to the lumbosacral defecation centre could lead to constipation. They support the authors’ own hypothesis (Naitou et al. 2015) that descending spinal pathways involved in suppression of nociceptive stimuli within the intestine (such as those involving dopaminergic or noradrenergic neurons) could also increase bowel movements, arguably to remove the stimulus by defecation. By highlighting an important pathway (interactions between descending spinal pathways, the spinal defecation centre, pelvic parasympathetic neurons and the colon/rectum) the experiments may also help to identify new treatments for chronic constipation and perhaps also for conditions such as irritable bowel syndrome where disturbances in bowel habit accompany abdominal pain. A potential role for descending spinal dopaminergic neurons in the mechanisms of chronic constipation during Parkinson's disease provides an alternative to the idea that these symptoms are predicted and/or caused by vagal nerve degeneration, by the presence of phosphorylated α-synuclein within the enteric nervous system and/or by a decline in dopaminergic enteric neurons (Jost, 2010; Visanji et al. 2014). This is important because there is currently little agreement between the presence or absence of phosphorylated α-synuclein (e.g. Pouclet et al. 2012; Shannon et al. 2012; Visanji et al. 2015) or dopaminergic markers (Singaram et al. 1995; Corbillé et al. 2014) in gastrointestinal biopsies from patients with Parkinson's disease, compared with appropriate control tissues. Chronic constipation, defined by continuous symptoms over a period of three or more months (Grey, 2011), is a common symptom that may be caused by a variety of conditions including neuropathies of the central nervous system (e.g. Parkinson's disease, spinal cord damage, multiple sclerosis), certain metabolic conditions and by disorders within the gut itself (e.g. scleroderma) (Winge et al. 2003; Sethi et al. 2014). Constipation is also a side-effect of many important classes of medication, including the opioid-based analgesics, certain tricyclic antidepressant medications and calcium channel blockers (Wawruch et al. 2012). Further, the prevalence of chronic constipation, from whatever cause, increases significantly in the elderly population (Gallagher & O'Mahony, 2009). For some of these patients, new treatments have recently been introduced (see Eswaran et al. 2014), acting via different mechanisms within the intestine itself (e.g. prucalopride acting as an agonist at 5-HT4 receptors within the enteric nervous system, lubiprostone activating chloride channel protein 2 to promote water secretion into the intestinal lumen, linaclotide also increasing chloride and water secretion by activation of the guanylate cyclase type-C receptor, and elobixibat, a bile acid transport inhibitor that by reducing reabsorption of bile acids increases their delivery to the colon where they can act to stimulate motility and secretion). However, alternatives are required for the many patients who respond poorly to these drugs (Pustovit et al. 2014), for those patients with gradually worsening or profound constipation caused by neuropathy (see above) and also for those with severe intestinal dilatation (post-operative ileus, megacolon and pseudo-obstruction; Broad et al. 2013). Spinal descending pathways may also play a role in disorders such as irritable bowel syndrome (IBS), defined symptomatically by the occurrence of abdominal pain with accompanying disturbance in bowel functions, but without a recognised pathology (Chang et al. 2014). Thus, Naitou et al. 2015 previously suggested that in rats a nociceptive stimulus to the intestine activates descending spinal inhibitory pathways to supress the noxious input and increase movements of the bowel to remove the stimulus by defecation. The authors focused on the descending noradrenergic neurons (arising from the pons) and suggested that the released noradrenaline acts at α1-adrenoceptors expressed by sacral parasympathetic neurons to stimulate propulsive movements of the colorectum; such a pathway may be of relevance to the mechanisms of IBS. The work of Naitou et al. (2015, 2016) not only highlights a pathway by which intestinal functions can be controlled, but may also help to define new therapeutic opportunities. Here, the focus would be the lumbosacral area of the spinal cord involved in the mechanisms of defecation. Naitou et al. (2016) used dopamine D1 and D2 receptor agonists (respectively, SKF38393 and quinpirole) and antagonists (SCH23390, haloperidol) to define a role for the D2-like family of receptor (D2, D3 and D4 receptors) in mediating the actions of the released dopamine. Further experiments are now required to define the exact receptor subtype, in addition to the possibility of a changed pharmacology caused by dopamine receptor dimerization or biased receptor interactions (see Brust et al. 2015; Maggio et al. 2015). The earlier work of Naitou et al. (2015) also defined a role for the α1-adrenoceptor in interfacing between spinal descending pathways and sacral parasympathetic nerve activity, and clearly many other opportunities could exist. Of particular note are the recent demonstrations of an ability of ghrelin to promote defecation by acting at ghrelin-sensitive neurons in the lumbosacral region of the rat spinal cord, stimulating pelvic nerve activity to promote propulsive contractions of the colorectum (Shimizu et al. 2006; Pustovit et al. 2014; Naitou et al. 2015). This activity has also been demonstrated with ghrelin in rats with diet-induced constipation (Pustovit et al. 2015), spinal cord damage (Ferens et al. 2011) and constipation induced by 6-hydroxydopamine, a model of Parkinson's disease (Karasawa et al. 2014). Interestingly, these animal studies also suggest that different compounds have markedly different durations of action, suggestive of differences in how they can interact with the receptor; ghrelin receptor agonists for treatment of constipation and other disorders are now in clinical trials (Sanger & Furness, 2016). In summary, the data presented by Naitou et al. (2016) offer a fresh perspective into the possible mechanism of the chronic constipation experienced by patients with Parkinson's disease. It is now essential to translate their hypothesis by studying models of Parkinson's disease and, eventually, patients with the disease itself. It is also important to fully understand other mechanisms by which the spinal defecation centre can be controlled and of course, isolate the dopamine and other receptors and drug targets which might offer the potential to develop much-needed new treatments for patients with chronic constipation (especially those with profound neuronal damage: Parkinson's disease, patients with spinal damage or multiple sclerosis). Again, translation is all important. Thus, it should be noted that the current data have been obtained largely by studies using rodents, in which the gastrointestinal physiology has many similarities to humans but also important differences which can complicate their translational value (Sanger et al. 2011). Nevertheless, the recent work with ghrelin receptor agonists may at least partly represent the beginning of this translational process since early studies in humans also indicate increased defecation in response to the ghrelin receptor agonists ulimorelin, relamorelin and capromorelin (see Sanger & Furness, 2016, for references). Together with the new work of Naitou et al. (2016) these studies bring new insights not just in the mechanisms of constipation but perhaps also in functional bowel disorders where the aetiology of the disease is not clear, such as IBS. None declared. The author currently receives funding from The Dunhill Medical Trust; The Research into Ageing Fund, set up and managed by Age UK; the BBSRC (Case award with GlaxoSmithKline); and Takeda pharmaceuticals.