Introduction

The coupling of both secretory and motility activities of the different sections of the gastrointestinal and the biliary and pancreatic segments of the digestive tract favors the parallelism of the digestive, absorptive, and motility activities that guarantee the maximal utilization of the ingested nutrients. However, it should also guarantee the descending gradient of pressure, which allows the normal progression of the nutrients with a minimum of waste. This physiological target is accomplished because the different segments of the digestive tract (esophagus, stomach, duodenum, small bowel, colon, and rectum) are separated by adequate sphynctereal rings that should be chronologically opened and closed in order to allow the progression and impede refluxes of the ingested food. In addition to the above, the hepato-biliary and pancreatic flowings should pass over the biliary and pancreatic ductular channels before reaching the choleducus, at which end the sphincter of Oddi acts as a semaphore that requires several neuroautonomic and hormonal requirements before giving the green light to allow the flow of the biliary and pancreatic juice to the duodenum. Accordingly, these complex motility and secretory mechanisms guarantee the sequential functioning of the different branches of the digestive tract addressed to allow an adequate performance of the digestive and absorptive processes; however, taking into account the many physiological factors (hormonal as well as ANS) that interact at these levels, it would be easy to understand the lability of the above functioning, which is submitted to many types of stressor agents able to interfere with the physiology of the ANS, which is responsible for it. Special mention should be made of the iatrogenic pharmacological manipulations that should be included among the most frequent causes of gastrointestinal diseases [1–3].

Neuroautonomic and Hormonal Factors Involved in the Gastrointestinal and Pancreato-Biliary Physiology

Esophageal motility and emptying depends on the esophageal-gastric sphincter, which contracts and relaxes according to the intra-gastric pH. Contractile response is registered when the pH is low and tends to relax when it rises. It is maximally open when gastric acid disappears. The fact that the enhancement of gastric acidity tends to close the pyloric sphincter also indicates that both the esophageal and the duodenal mucosa should be protected from the gastric acid secretion. Conversely, the duodenal mucosa is physiologically adapted to the alkalinity of the pancreato-biliary secretion, which is able to neutralize the acidity of the gastric shove in such a way that an adequate intermission of the pyloric sphincter aperture grants the necessary accomplishment of the neutralization of the gastric acid flow. Impairment of this physiological mechanism favors the ulceration of the duodenal mucosa. Conversely, the disappearance of the gastric acid content facilitates the duodenal-gastric reflux of bilis, bicarbonate, and pancreatic enzymes, which are able to damage both gastric and esophageal mucosa. This phenomenon is frequently registered in patients taking omeprazole and any other similar drugs [4].

Hormonal factors also play both physiological and pathophysiological roles. Gastrin enhances both gastric acid and pancreato-biliary flowing. Conversely, duodenal hormones such as secretin, pancreozymin, and cholecystokinin (CCK) enhance pancreato-biliary secretions as well as gallbladder and biliary motility. However, these hormones are coupled with the ANS mechanisms into a complex physiological interaction in such a way that any ANS disorder triggers the physiological unbalance responsible for different gastrointestinal and pancreato-biliary dysfunctions [5, 6]. In addition, it has been demonstrated that CCK plays primordial physiological and pathophysiological roles in the motility of the colon [7, 8]; in addition, this gastrointestinal hormone crosses the blood brain barrier, at which level it interacts with CCK receptors located at the dorsal raphe serotonergic nucleus DR-5HT and provokes satiety [9, 10]. Underlying this physiological phenomenon is the reduction of both gastrointestinal motility and secretions and the inhibition of the distal colon motility. Thus, physicians should be aware that the pharmacological manipulation of drugs addressed to treat gastrointestinal diseases provokes both peripheral and CNS effects.

According to the above, we will try to summarize the most relevant pathophysiological and neuropharmacological mechanisms underlying gastrointestinal and pancreato-biliary disorders as well as the hormonal plus the ANS and CNS mechanisms associated with them. In addition, we will try to introduce readers into the most relevant factors that interact with both the CNS and the ANS areas.

The Peripheral Autonomic Nervous System (ANS)

Whereas the sympathetic activity depends on two peripheral branches, neural and adrenal [11], parasympathetic activity is displayed by nerves that release acetylcholine (ACh) [3]. However, serotonin (5HT) released from the enterochromaffin cells during parasympathetic excitation is able to antagonize peripheral sympathetic activity [12]. In addition, 5HT-neurons located at the myenteric plexa send excitatory axons to the muscular longitudinal external intestinal layer [13, 14]. Furthermore, 5HT released from the enterochromaffin cells excites pancreatic exocrine [15–19] and inhibits pancreatic endocrine secretion [20–22], respectively.

Sympathetic nerves arise from the lumbar sympathetic acetylcholinergic (ACh) neurons, whereas adrenal glands receive excitatory axons from the thoracic sympathetic ACh-neurons [23]. The former sympathetic branch receives excitatory axons from the A5-NA nucleus (located at the pontomedullary area), whereas the adrenal sympathetic branch receives excitatory axons from the C1-Ad medullary nuclei [24, 25]. Thus, taking into account that sympathetic nerves release 80% of noradrenaline (NA), whereas adrenal glands secrete 80% of Ad, the NA/Ad plasma ratio reflects the proportional participation of both sympathetic branches [26]. In addition, considering that the A5-NA and the C1-Ad nuclei interchange inhibitory axons [27], it should be easy to understand that the assessment of the circulating catecholamines should afford adequate information about the proportional participation of these two sympathetic branches [28, 29]. Finally, it should be known that, whereas the A5-NA neurons send inhibitory axons to the medullary vagal (ACh) nuclei [30, 31], the C1-Ad nuclei send and also receive axons from the medullary vagal complex [27, 32].

The above-summarized crosstalk explains the fast alternancy frequently registered between the adrenal sympathetic versus parasympathetic activity as well as the slow alternation that might occur between the other binomial (neural sympathetic vs. parasympathetic) [29]. In addition, it should be remembered that both NA and Ad axons inhibit Ad and NA postsynaptic neurons, respectively, which are crowded with alpha-2 inhibitory receptors [33]. This pharmacological data explains why alpha-2 agonists and/or antagonists are able to interfere with both types of sympathetic predominance.

According to the above-summarized information, it is understandable that an adequate assessment of the ANS disorders should include the determination of all circulating neurotransmitters. With respect to this, we report that our institute has assessed those parameters in some 30,000 normal and diseased subjects, not only during supine-resting (fasting) conditions, but also after many types of challenges (orthostasis, exercise, oral glucose, and many CNS-acting drugs) [34–47].

Although acetylcholine is not detectable in the peripheral blood, the assessment of both plasma and platelet serotonin (f-5HT and p-5HT) affords adequate information about this parasympathetic parameter. However, considering that increased platelet aggregation triggers the enhancement of f-5HT registered during stress periods, which depends on the raised levels of plasma Ad [42, 44, 48], the assessment of f-5HT carried out during non-stress periods reflects parasympathetic activity, because plasma ACh competes with serotonin for platelet uptake. In other words, f-5HT is positively correlated with plasma ACh levels [49–53]. Cardiovascular parameters parallel ANS disorders. For instance, heart rate is positively correlated with adrenal sympathetic activity, whereas diastolic blood pressure depends on neural sympathetic activity. With respect to this, we have demonstrated that an accurate assessment of these cardiovascular parameters at the 1-min orthostasis challenge affords information that allows knowing which of the two peripheral sympathetic branches is predominant [28, 36–38].

Pathophysiological Data Related to Some Gastrointestinal Diseases

Gastritis

Type A (antral) gastritis is frequently underlain by a TH-2 immunological profile (adrenal sympathetic overactivity) and is frequently associated with duodenal ulceration [54, 55]. Parasympathetic rebounds, always registered during nocturnal (sleep) periods, are responsible for the appearance of duodenal ulcers [1, 2, 56–59]. In our long experience with this issue, the attenuation of both the diurnal adrenal sympathetic and the nocturnal parasympathetic rebounds is enough to revert both the uncoping stress situation and the gastroduodenal damage. This target is reached through neuropharmacological therapy, which includes small doses of NA uptake inhibitors (at diurnal period) plus small doses of NA and 5HT uptake inhibitors before bed. With respect to the above, it should be remembered that the iatrogenic effect triggered by drugs that interfere with the K+ and NA+ versus H+ pumps interchange destroys the mucosal barrier, provokes the disappearance of antral acidity, and facilitates duodeno-gastric reflux because of the permanent antral alkalinity [59–61]. In addition, evidence has demonstrated that helicobacter pylori favors the TH-1 immunity profile, which protects against malignancy [62]. Furthermore, the gastric to esophageal reflux of bilis is responsible for esophagitis, which is also provoked by this iatrogenic factor. The esophagic sphincter remains open because of the alkalinization of the gastric content. This phenomenon is enhanced during the recumbent nocturnal periods when parasympathetic predominance increases alkaline-pancreato-biliary secretions. This iatrogenic phenomenon is more evident in cholecystectomized patients, because bilis is not stored in the gallbladder. Accordingly, we believe that an adequate neuropharmacological therapy is the only therapeutical strategy able to revert the above-mentioned iatrogenic deleterious pathophysiologic disorders [4, 33, 63–70].

Additional information has demonstrated that type B gastritis is present in subjects affected by neural sympathetic predominance. These subjects present with a TH-1 immunological profile because they have low levels of circulating Ad. This catecholamine favors the appearance of malignant diseases because it interferes with the destruction of malignant cells by the natural killer (NK) cells. This issue was demonstrated and published by our research group in 1987 [24, 42, 71–79] and has been confirmed by other researchers [80]. Thus, any neuropharmacological therapy of patients affected by malignant diseases should include the reversion of the adrenal over the neural sympathetic predominance.

Reflux Esophagitis

This disorder is also underlain by diurnal adrenal sympathetic overactivity that is reversed by parasympathetic overactivity in the nocturnal periods. Hence, these patients should also be treated with neuropharmacological manipulation addressed to enhance diurnal neural sympathetic activity. With respect to the above, we should emphasize that the nocturnal parasympathetic rebound, always registered in these patients, allows the duodenal and gastric reflux to the esophagus because the neural sympathetic hypoactivity allows the permanent aperture of both the pyloric and cardial sphincters [81, 82]. This phenomenon obliges attempting the normalization of the sleep disorder that is always present in these patients. With respect to this, it has been exhaustively demonstrated that in normal subjects, adrenal sympathetic activity reaches near zero values 10–15 min after the supine-resting state [34, 64, 69, 70]. On the contrary, neural sympathetic activity (which closes the sphincter) fades gradually and reaches minimal values (never zero values) at the REM sleep periods (90 min after the sleep initiation) [34, 83]. Thus, the absence of the slow wave sleep (SWS) period always registered in stressed mammals [84] interferes with the sphincter closure and favors biliary-gastro-esophageal reflux. Accordingly, normalization of the sleep disorder should constitute an imperative therapeutic step, addressed to reach the above target. However, a scientific neuropharmacological manipulation, but not the administration of benzodiazepines, should be prescribed. With respect to this, we would refer readers to our last books [24, 25].

With respect to the above, we will summarize the CNS disorders responsible for the raised levels of adrenaline and cortisol registered in stressed patients. The raised cortisol plasma levels depend on the hypersecretion of corticotropin-releasing hormone (CRH) by the hypothalamus. Dorsal raphe axons release serotonin at this level, which excites CRH neurons. In addition, DR-5HT axons excite also the C1-Ad nuclei, which enhance adrenal sympathetic activity [85]. Over-excitation of the C1-Ad nuclei (adrenal sympathetic activity) inhibits the A5-NA nucleus, which is responsible for the peripheral neural sympathetic activity. Thus, any neuropharmacological treatment of the stress situation should include the reversion of the C1-Ad over A5-NA predominance. This target is reached with the administration of a small dose of drugs that inhibits the uptake of NA at diurnal periods and a small dose of drugs that inhibits both the NA and the 5HT uptake at nocturnal periods. This manipulation also improves the sleep cycle. The above neuropharmacological strategy fits well with the successful neuropharmacological treatment of duodenal ulcer with doxepin (inhibits both NA and 5HT uptake) reported many years ago [61] and since then further confirmed.

Irritable Bowel Syndrome and Biliary Dyskinesia

Neural sympathetic activity contracts pyloric, ileocecal, and Oddi sphincters and, in addition, contracts the sigmoidal rectal junction. At the same time, this branch of the peripheral autonomic nervous system (ANS) antagonizes the dilator effect triggered by CCK at these levels; hence, overactivity of this ANS branch interferes with the CCK released during the postprandial periods and interrupts the biliary, ileal, and sigmoidal flow to the post-junctional segments [5, 7, 8, 86–90]. The above phenomena are registered during the spastic colon period of the IBS. The fact that clonidine, a CNS-acting alpha-2 agonist that suppresses both neural and adrenal sympathetic overactivities by acting at the A5-NA and/or C1-Ad CNS nuclei, supports our postulation [87–102]. Both CNS nuclei are crowded by alpha-2 inhibitory receptors; hence, the drug would act at the hyperactive, but not at the hypoactive nucleus. Furthermore, considering that both CNS nuclei interchange inhibitory axons, alpha-2 agonists and/or antagonists are able to revert the physiological predominance of any of both systems. In addition, it is important to know that whereas the C1-Ad nuclei are positively correlated with the dorsal raphe (DR) serotonergic nucleus, the A5-NA nucleus parallels the activity of the median raphe (MR) serotonergic nucleus (MR-5HT) [103, 104]. Finally, it should be known that both serotonergic nuclei interchange inhibitory axons. Summarizing the above, it has been established that whereas the DR-5HT + C1-Ad hyperactivity is responsible for the uncoping stress syndrome, the MR-5HT + A5-NA binomial predominates in patients affected by endogenous depression as well as in patients affected by neural sympathetic overactivity (essential hypertension, hyperinsulinism, rheumatoid arthritis, and all TH-1 autoimmune diseases) [3, 24, 101–105]. At the gastrointestinal level, patients with reflux esophagitis [81, 82], duodenal ulcer [59, 60], ulcerative colitis [100, 106], and diarrheic periods (IBS) [88, 107, 108], as well as showing mucosal eosinophilia, always present adrenal sympathetic predominance and a TH-2 immunological profile, whereas patients affected by the spastic colon, biliary hypokinesia (no gallbladder emptying), Crohn’s disease, etc., always have both underlying neural sympathetic predominance and TH-1 immunological profile [24, 25, 72, 94, 105, 109]. The above neuroautonomic and immunological information has allowed us to successfully treat hundreds of patients affected by such gastrointestinal disorders [108–115] (Table 1, Figs. 1, 2).

Table 1 Neuroautonomic plus immunological profiles underlying gastrointestinal and pancreato-biliary diseases
Full size table
Fig. 1
figure 1

Experimental evidence: physiological, pathophysiological, neuropharmacological, clinical, and therapeutic evidence dealing with the irritable bowel syndrome and biliary dyskinesia. Effects of the intramuscularly injected CCK (0.5 U/kg). CCK triggered the gallbladder to empty in a normal subject (upper). One week later, dihydroergotamine (DHE 1 mg) intramuscularly injected 45 min before CCK interfered with the gallbladder emptying (lower) and in addition provoked abdominal pain at the right-upper abdominal side. At the plasma level, DHE provoked a significant rise of the plasma noradrenaline (NA) and an increase of the NA/Ad plasma ratio (neural sympathetic overactivity). Furthermore, significant reduction of the f5HT/p5HT ratio (hypo-parasympathetic activity) was registered after DHE administration. Finally, the above circulating neurotransmitters profile triggered by DHE administration was further reverted after clonidine administration

Full size image
Fig. 2
figure 2

Effects of clonidine on the distal colon and biliary motility of a patient affected by spastic colon syndrome plus biliary dyskinesia. Clonidine (0.15 mg intramuscularly injected) suppresses the diarrheic syndrome in a patient affected by irritable bowel syndrome (diarrheic period). Clonidine suppressed also the rectal hyperactivity and enhanced the sigmoidal tone (sigmoidal rectal junction). The X-ray study, carried out 3 days before this test, showed a normal gallbladder emptying after the Boyden (test) meal. However, the administration of oral clonidine (0.15 mg three times daily) reverted not only the distal colon motility profile, but also the diarrheic syndrome, and, in addition, triggered an increase of the sigmoidal tone plus the rectal hypomotility. No gallbladder emptying was registered during a second radiological study performed 8 days later during the clonidine trial (at which period the patient presented constipation and abdominal pain at both the right-upper hypochondrium and the left-lower abdominal zone). Further, a small dose of mianserine (an alpha-2 central-acting antagonist) intramuscularly injected reverted both the gallbladder and the colonic spasticity and in addition suppressed abdominal pains [12, 96]

Full size image

Hyperactivity of the adrenal sympathetic system underlies the diarrheic period of the IBS. At this stage, gastrointestinal and pancreatic sphincters remain open. The continued overflow of bilis is diverted to the duodenum; however, some fraction may reflux to the stomach and esophagus, whereas some other fraction of the biliary flow is discharged into the small bowel, at which level it enhances motility. The resultant hyper-peristalsis is enhanced by the inhibition of the release of serotonin from the myenteric plexa level [14]. These neurons send excitatory axons to the longitudinal muscular intestinal layer (which increases intestinal tone and interferes with peristalsis); thus, depletion of this serotonergic plexus reduces intestinal tone and facilitates peristalsis, which depends on the circular muscular layer. Considering that neural sympathetic and adrenal sympathetic activities are positively correlated with the above muscular layers, respectively, the disappearance of the spasticity (which depends on the external muscular layer) favors the activity of the circular (internal) muscular layer that enhances peristalsis. Summarizing the above, neural sympathetic activity is positively correlated with the myenteric (5HT) and longitudinal muscular layer responsible for the intestinal tone, whereas adrenal sympathetic activity favors intestinal hypotony and peristalsis [18, 116–120] (Figs. 3, 4).

Fig. 3
figure 3

Adrenal sympathetic activity. This peripheral branch of the autonomic nervous system (ANS) depends on the secretion of catecholamines by the adrenal gland (80% of Ad + 20% of NA + 10% DA). These glands receive excitatory axons from the thoracic presynaptic (ACh) neurons. These ACh neurons depend on the excitatory drives arising from the C1-Ad medullary nuclei, which in addition send inhibitory axons to both the A5(NA) and the A6(NA) nuclei. Furthermore, these subjects also present raised levels of plasma cortisol (CRT), which depends on the DR-5HT axons. This serotonergic nucleus interchanges excitatory drives with the C1(Ad) nuclei. Finally, both DR(5HT) and C1(Ad) axons excite the hypothalamic paraventricular nucleus. Furthermore, cortisol crosses the blood brain barrier and excites the DR-5HT. This positive feedback explains the raised levels of circulating Ad and CRT always registered in these patients. The above anatomical and physiological and pathophysiological mechanisms are reverted by administration of NA uptake inhibitors such as desipramine. Finally, the raised levels of Ad and CRT in the plasma are consistent with the bulk of clinical syndromes underlain by the uncoping stress syndrome

Full size image
Fig. 4
figure 4

Neural sympathetic activity. Neural sympathetic activity depends on the sympathetic nerves' release of NA (90%) + DA (10%). This branch of the peripheral autonomic nervous system (ANS) is positively correlated with activity of the ponto-medullary A5(NA) neurons, which excite the spinal sympathetic neurons and inhibit the C1(Ad) medullary nuclei (responsible for the adrenal glands secretion). In addition, A5(NA) axons inhibit the medullary vagal complex. The absence of C1(Ad) activity redounds in the hypoactivity of the DR(5HT) neurons. Serotonin released from these axons is the most important factor that initiates and prolongs the CRH secretion by the PVN hypothalamic nucleus. The minimization of this factor is consistent with the moderated rise of plasma CRT always registered during neural sympathetic overactivity. In addition, it has been demonstrated that sympathetic nerves inhibit adrenal gland secretion, directly by acting at alpha-2 receptors located at these glands. This is consistent with the raised NA/Ad plasma ratio registered in these patients. Furthermore, overactivity of the sympathetic nerves provokes the vascular, bronchial, sphincteral (gastrointestinal, urinary) contraction always present at this circumstance

Full size image

At the CNS level, a great bulk of data allows associating neural sympathetic activity with the MR-5HT nucleus, whereas the adrenal sympathetic activity parallels the DR-5HT nucleus activity. Predominance of the former is associated with depression, whereas the latter CNS circuitry predominates during the uncoping stress syndrome [25, 39–41, 43, 44, 88, 103, 104, 121–124]. These findings fit well with the psychiatric profiles registered during both types of IBS clinical periods. The above comments are supported by the routine assessment of circulating neurotransmitters in some 30,000 normal and diseased subjects, not only during supine-resting condition but also after many types of stressor agents and CNS-acting drugs [35, 37, 44, 46, 123, 125–127].

In summary, the assessment of circulating neurotransmitters carried out in our institute throughout the last 30 years showed that a lowered NA/Ad ratio (<3) is registered during the diarrheic period, whereas the high NA/Ad ratio (>7) is found during the spastic colon period [39–41, 43, 88, 120, 122, 128, 129].

Both the raised plasma serotonin (f5HT) and the reduced platelet serotonin (p5HT) levels registered during the diarrheic periods were reverted at the spastic colon period. The reversion of the above serotonin parameters should be associated with the reduction of platelet aggregation, which also paralleled the raised levels of circulating adrenaline, and in addition, to the fading of the adrenal sympathetic activity, which triggers platelet aggregation; thus, serotonin stored in the platelets is released to the plasma and further metabolized.

Commentary Dealing with the Pathophysiology and Therapeutical Approaches of Pancreatic Inflammatory Diseases as Well as the Carcinoid Syndrome

Pancreatitis

We have successfully treated 41 patients affected by acute pancreatitis; all patients have done well throughout the last 4 decades. All symptoms disappeared abruptly after the first intramuscular injection of clonidine (0.15 mg); plasma amylase levels were normalized within the first 6 h. Clonidine was administered every 6 h throughout the first 48 h, and then it was progressively spaced. The dramatic improvement triggered by this alpha-2 (CNS-acting) agonist should be attributed to facts showing that the pancreatic innervation depends on the C1-Ad medullary nuclei, which also innervates salivary glands. The latter is consistent with findings showing that clonidine triggered dry mouth [130, 131]. In addition, we demonstrated that clonidine relieves all types of pancreatic pain, which should be attributed to the reduction of the flow of pancreatic juice [6–8, 15–17, 20–22, 45, 51, 87, 89, 90, 95–97, 107, 109, 121, 131–147].

Carcinoid Syndrome

We have successfully treated nine patients affected by this disease (no failures). Our neuropharmacological therapeutic strategy is addressed to reduce the overwhelming parasympathetic activity that underlies this syndrome. This target was reached through the enhancement of the neural sympathetic activity that annuls both the adrenal and parasympathetic oscillations always registered in these patients [18, 19, 148]. With respect to the above, it is well established that parasympathetic nerves excite enterochromaffin cells. Serotonin released by these cells to the portal vein is partially uptaked by the liver; however, some fraction escapes to this obstacle and reaches the lung at which level some other fraction of 5-HT is taken up by the pulmonary neuroendocrine cell (PNEC). The serotonin that escapes from lung and platelet uptake remains free in the plasma (f-5HT) and excites medullary area postrema (AP), which is located outside the blood brain barrier [116, 119]. The excitation of this nucleus, which is crowded by 5HT3 receptors [149], triggers the activation of the medullary vagal complex (nucleus tractus solitarii = NTS), which is responsible for the hyper-secretion of serotonin by the enterochromaffin cells (Bezold-Jarisch reflex). The neuropharmacological manipulation addressed to enhance neural sympathetic activity (NA plasma level) provokes sustained clinical improvement plus the significant reduction of circulating serotonin [15, 17–19, 141, 150, 151].

Not only the carcinoid syndrome, but also cystic fibrosis, pancreatic and hepatic cysts have been successfully treated with the same neuropharmacological manipulation. These findings are consistent with the demonstration that the two latter diseases are underlain by raised levels of circulating serotonin as well as by lower NA plasma values. The above results indicate that adrenal sympathetic and parasympathetic over neural sympathetic predominance is responsible for the hyperactivity of the enterochromaffin cells that provokes the physiological disorders underlying carcinoid syndrome and cystic fibrosis of the pancreas [15–17, 131–133]. The above phenomena depend on the excitation of the C1-Ad nuclei by ACh-NTS axons [152, 153].