Central sensitisation in visceral pain disorders

Nevner hvordan IBS skaper sentralsensitering og hyperalgesia andre steder enn bare tarmen, og bidrar til mange muskel- og ledd problemer. Nevner at dette spesielt skjer i korsryggen hvor sensoriske nerver fra tarmen treffer samme nerve i ryggmargen som de sensoriske nervene fra beina.


The concept of visceral hyperalgesia has been examined in a variety of functional gastrointestinal disorders (FGIDs), including oesophagitis, gastro‐oesophageal reflux disease, non‐ulcer dyspepsia, gastroparesis, and irritable bowel syndrome (IBS). Visceral hypersensitivity has also been demonstrated in non‐gastrointestinal disorders such as interstitial cystitis and ureteric colic.1 Although the pathophysiological mechanisms of pain and hypersensitivity in these disorders are still not well understood, exciting new developments in research have been made in the study of the brain‐gut interactions involved in the FGIDs.

In this issue of Gut, Sarkar and colleagues2 address the phenomenon of temporal summation of pain, termed “wind‐up”, and its relationship to central sensitisation and secondary visceral pain hyperalgesia caused by acidification of the oesophagus (see page 920). Also in this issue of Gut, Drewes and colleagues3 examine peripheral and central sensitisation using both mechanical and thermal stimuli in patients with oesophagitis compared with control subjects (see page 926). They found that in patients with oesophagitis, the interaction between central and peripheral nociceptive input may help explain patient symptoms. Understanding the implications of these two studies requires examining the concept of central sensitisation in visceral pain disorders. Both of these studies have important clinical and research ramifications for the study of FGIDs.

“Hypersensitivity in IBS patients is not just limited to the gut and more widespread alterations in central pain processing may be involved in this chronic pain disorder”

The most pronounced hyperalgesia appears to occur at the lumbosacral level at which colon and lower extremity nociceptive afferents are likely to converge onto common spinal segments, explaining why patients had higher thermal hypersensitivity in the foot than in the hand (see fig 11).14,15,19

High Energy Diets-Induced Metabolic and Prediabetic Painful Polyneuropathy in Rats

Nevner hvordan høy-fett høy-karbo forværrer nevropati (ødelagte nerver), men høy-fett høy-karbo høy-salt ser ut til å dempe smertene noe.



In the current study, early metabolic syndrome (hyperinsulinemia, dyslipidemia, and hypertension) and prediabetic conditions (IFG) could be induced by high energy (high-fat and high-sucrose) diets in rats which later developed painful polyneuropathy that was characterized by myelin breakdown and LMF loss in both peripheral and central branches of primary afferent neurons. However, SMF and UMF were far less damaged in the same rats. The phenomenon that the high energy diets only induce mechanical, but not thermal, pain hypersensitivity may reflect a selective damage to LMF, but not to the SMF and UMF. Moreover, dietary sodium (high-salt) deteriorates the neuropathic pathological process induced by high energy diets further, but paradoxically high salt consumption may improve, at least temporarily, chronic pain perception in these animals.

We have therefore established a strong link between high-energy/high-salt diet induced metabolic syndrome and prediabetes which results in relatively selective LMF damage in both the PNS and CNS that in turn can result in neuropathic pain. These results have a profound impact on patient welfare relative to diet choice, not just for T2DM onset, but also for its associated neuropathic symptoms.

Inflammatory Cytokine Concentrations Are Acutely Increased by Hyperglycemia in Humans

Denne viser hvordan selv de uten diabetes får økt cytokinverdi (betennelse) i blodet i 1-2 timer etter blodsukkerstigning. I denne studien var det snakk om blodsukker over 15 mmol/L. De sier at blodsukker økninger påvirker cytokinnivået mer enn et stabilt høyt blodsukker.


Control Subjects:

Plasma IL-6 levels rose from a basal value of 2.0±0.7 pg/mL to a peak of 3.1±0.9 pg/mL at 1 hour (P<0.01) and returned to basal level at 3 hours (Figure 2).

Fasting plasma TNF-α levels were 3.3±1.2 pg/mL; they peaked at 1 hour (4.9±1.4 pg/mL, P<0.01), and returned to baseline at 3 hours.

Plasma IL-18 levels rose from a basal value of 116±28 pg/mL to a peak of 140±31 pg/mL at 2 hours (P<0.01) and returned to basal levels at 3 hours (110±26 pg/mL).

The novel findings of the present study were that (1) acute hyperglycemia in control and in IGT subjects induces an increase in plasma IL-6, TNF-α, and IL-18 concentrations; (2) the effect of sustained hyperglycemia is reproduced by transient oscillations in plasma glucose and is amplified by the IGT status; and (3) the antioxidant glutathione completely prevents the rise in plasma cytokines induced by hyperglycemia. These results indicate that hyperglycemic spikes affect cytokine concentrations more than continuous hyperglycemia, at least in the short term, and suggest that an oxidative mechanism mediates the effect of hyperglycemia.

Another finding of the present study was that glutathione, a powerful antioxidant, completely prevented cytokine increase induced by oscillatory hyperglycemia in healthy humans. Hyperglycemia-induced oxidative stress, 32 along with soluble advanced glycation end products and products of lipid peroxidation, possibly serves as a key activator of upstream kinases, leading to induction of inflammatory gene expression.33

Hyperglycemia enhances the cytokine production and oxidative responses to a low but not high dose of endotoxin in rats.

Denne beskriver hvordan hyperglycemi (regnes som blodsukker over 7 mmol/L i lengre perioder, eller fastende blodsukker over 7) gir økt cytokin-aktivitet i flere timer etter en stressende episode. Om man spiser en snickers går blodsukkeret opp til over 10, og om man kontinuerlig spiser mat som øker blodsukkeret er det en stor sjangse for at man har en kronisk betennelsesreaskjon med økt cytokin aktivitet.

Kobler vi det med denne, som nevner at cytokiner tilført fra utenfor muskelen kan gi hyperalgesi, så begynner bildet å bli klarere: «One mechanism of action, the immune-to-brain communication through activation of brain and spinal cord glial cells was reviewed by Wieseler-Frank et al. (2005). Activation of CNS glia and subsequent production of inflammatory cytokines can lead to hyperalgesia.» http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1552097/



The aim of this study was to investigate whether hyperglycemia enhances the systemic inflammatory response and oxidative stress induced by endotoxin.


Laboratory investigation.


University medical school.


Forty-one male Sprague-Dawley rats.


A hyperglycemic condition was produced in rats by glucose clamp for 3 hrs. Immediately on stopping the glucose infusion, animals received different doses of endotoxin injection (0, 0.2, or 1 mg/kg), and then blood glucose concentration was monitored over the ensuing 2 hrs. At the end of 2 hrs, levels of tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, corticosterone, and alpha-1 acid glycoprotein were determined in serum, and malondialdehyde and total glutathione content were determined in the liver.


Over the 2-hr period, blood glucose concentrations returned to normal in initially hyperglycemic rats. However, the levels of cytokines, corticosterone, and alpha-1 acid glycoprotein were significantly higher in these animals compared with nonhyperglycemic controls, demonstrating an extended effect of prior hyperglycemia on markers of systemic inflammation. With low-dose (0.2 mg/kg) but not high-dose (1 mg/kg) endotoxin administration, hyperglycemic animals had significantly higher levels of cytokines compared with controls, indicating that prior hyperglycemia can enhance the systemic inflammatory response to a moderate endotoxin dose, but that the maximum effects of endotoxin on production of inflammatory cytokines are not altered by transient high glucose exposure.


Systemic inflammation persists for a period following hyperglycemia, and this can enhance the systemic inflammatory response to a subsequent moderate stress.

Noen studier om hvordan Substans P forholder seg til mat

Denne nevner at en 10% reduksjon av anbefalt daglig magnesium inntakt øker sjangsen for osteoporose og Substans P

Bone Loss Induced by Dietary Magnesium Reduction to 10% of the Nutrient Requirement in Rats Is Associated with Increased Release of Substance P and Tumor Necrosis Factor-α1 


These data demonstrated that a Mg intake of 10% of NR in rats causes bone loss that may be secondary to the increased release of substance P and TNF-α.

Denne nevner hvordan tiltak som reduserer SP bidrar til å redusere de negative virkningene av magnesiummangel.

Neurogenic Inflammation and Cardiac Dysfunction due to Hypomagnesemia.


Significant protection against most of these MgD-mediated events has been observed with interventions that modulate neuronal SP release or its bioactivity, and with several antioxidants (vitamin E, probucol, epicaptopril, d-propranolol). In view of the clinical prevalence of hypomagnesemia, new treatments, beyond magnesium repletion, may be needed to diminish deleterious neurogenic and prooxidative components described in this article.

Denne nevner hvordan SP er involvert i insulin regulering og diabetes.

Role of Substance P in the Regulation of Glucose Metabolism via Insulin Signaling-Associated Pathways


Our results demonstrate an important role for SP in adipose tissue responses and obesity-associated pathologies. These novel SP effects on molecules that enhance insulin resistance at the adipocyte level may reflect an important role for this peptide in the pathophysiology of type 2 diabetes.

Care and Feeding of the Endocannabinoid System: A Systematic Review of Potential Clinical Interventions that Upregulate the Endocannabinoid System

Denne beskriver endocannabinoider(eCB) og hvordan man kan øke produksjonen av dem og reseptorene for dem. eCB er et kroppens viktigste naturlige smertstillende stoffer som kan produseres og påvirker alle nerver i kroppen. Spesielt viktig i hjernen, men også i det perifere nervesystem.

Massasje, kiropraktikk og hard trening (f.eks. runners high) utløser eCB i kroppen. Det gjør også omegabalanse (mer n-3), probiotica, NSAIDs, m.m. Også yoga, meditasjon, pust og andre stressreduserende påvirker eCB. Og trening, men kun om man gjør det jevnlig over tid.

Den nevner at langvarig stress reduserer eCB i kroppen siden det er koblet til kortisol. Men den nevner også at noen tilstander kan ha forhøyet eCB i kroppen, f.eks. overvekt.

Med høyt nivå av n-6 relativt til n-3 blir det en overvekt av AA (arakidonsyre) som produserer en overvekt av eCB, som dermed fører til en reduksjon av eCB reseptorer. Dette gjør at smertestillende medikamenter fungerer dårligere, og at det blir lettere kronisk smerte. Tilskudd av n-3 gjør at eCB reseptorene øker. Studiene er gjort på mus og innebærer 17 g/kg.


The endocannabinoid (eCB) system consists of receptors, endogenous ligands, and ligand metabolic enzymes. Metaphorically the eCB system represents a microcosm of psychoneuroimmunology or mind-body medicine. Cannabinoid receptor 1 (CB1) is the most abundant G protein-coupled receptor expressed in the brain, with particularly dense expression in (rank order): the substantia nigra, globus pallidus, hippocampus, cerebral cortex, putamen, caudate, cerebellum, and amygdala [1]. CB1 is also expressed in non-neuronal cells, such as adipocytes and hepatocytes, and in musculoskeletal tissues. Cannabinoid receptor 2 (CB2) is principally associated with cells governing immune function, although it may also be expressed in the central nervous [2][3].

The eCB system’s salient homeostatic roles have been summarized as, “relax, eat, sleep, forget, and protect” [5]. It modulates embryological development, neural plasticity, neuroprotection, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and most importantly from the viewpoint of recent drug development: hunger, feeding, and metabolism. Obese individuals seem to display an increased eCB tone, driving CB1activation in a chronic, feed-forward dysfunction (reviewed by [6]).

Other diseases are associated with suboptimal functioning of the eCB system. Russo [8]proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent CEDS, “clinical endocannabinoid deficiency syndromes.” Fride [9] speculated that a dysfunctional eCB system in infants contributes to “failure to thrive” syndrome. Hill and Gorzalka [10] hypothesized that deficient eCB signaling could be involved in the pathogenesis of depressive illnesses. In human studies, eCB system deficiencies have been implicated in uncompensated schizophrenia [11], migraine [12], multiple sclerosis [13], Huntington’s [14],[15], uncompensated Parkinson’s [16], irritable bowel syndrome [17], uncompensated anorexia[18], and chronic motion sickness [19].

NSAIDs inhibit two cyclooxygenase (COX) enzymes, COX1 and COX2, and thereby block the conversion of arachidonic acid (AA) into inflammatory prostaglandins. Ibuprofen, ketorolac, and flurbiprofen also block the hydrolysis of AEA into arachidonic acid and ethanolamine [27]. SeeFigure 2. A binding site for some NSAIDs on FAAH has also been identified [28]. NSAID inhibition of COX2 blocks the metabolism of AEA and 2-AG into prostaglandin ethanolamides (PG-EAs) and prostaglandin glycerol esters (PG-GEs), respectively [29].

Combining NSAIDs with cannabinoids (either eCBs or exogenous cannabinoids) produces additive or synergistic effects. A sub-effective dose of WIN55,212-2 became fully antinociceptive following administration of indomethacin in rats [36].

In summary, preclinical studies indicate that some NSAIDs inhibit FAAH and enhance the activity of eCBs, phytocannabinoids, and synthetic cannabinoids. Combinational effects may be particularly relevant at peripheral sites, such as the peripheral terminals of nociceptors.

The distribution of glucocorticoid receptors (GRs) and CB1 overlap substantially in the central nervous system and other tissues, as do GRs and CB2 in immune cells. Dual activation of GRs and CBs may participate in glucocorticoid-mediated anti-inflammatory activity, immune suppression, insulin resistance, and acute psychoactive effects.

The acute administration of glucocorticoids may shift AA metabolism toward eCB synthesis in parts of the brain.

Chronic exposure to glucocorticoids downregulates the eCB system. Chronic corticosterone administration decreased CB1 densities in rat hippocampus [59] and mouse hippocampus and amygdala [61]. Chronic corticosterone administration in male rats led to visceral hyperalgesia in response to colorectal distension, accompanied by increased AEA, decreased CB1 expression, and increased TRPV1 expression in dorsal root ganglia. Co-treatment with the corticoid receptor antagonist RU-486 prevented these changes [62].

Polyunsaturated fatty acids (PUFAs) play fundamental roles in many cellular and multicellular processes, including inflammation, immunity, and neurotransmission. They must be obtained through diet, and a proper balance between omega-6 (ω-6) PUFAs and ω-3 PUFAs is essential. The typical Western diet contains a surfeit of ω-6s and a deficiency of ω-3s [130].

The inflammatory metabolites of AA are countered by dietary ω-3s. The two best-known ω-3s are eicosapentaenoic acid (EPA, 20:5ω-3) and docosahexaenoic acid (DHA, 22:6ω-3).

eCBs are derived from AA (see Figure 2). Several preclinical studies showed that dietary supplementation with AA increased serum levels of AEA and 2-AG, summarized in Table 1. Although we clearly need AA to biosynthesize eCBs, excessive levels of AA, administered chronically, may lead to excessive levels of eCBs. This in turn may lead to desensitized and downregulated CB1 and CB2 receptors.

Dietary supplementation with ω-3s predictably increased the concentration of EPA and/or DHA in tissues, cells, and plasma, and decreased the relative concentration of AA in tissues, cells, and plasma [132][133]. ω-3 supplementation also decreased AEA and 2-AG in tissues, cells, and plasma (Table 1).

Adequate levels of dietary ω-3s are required for proper eCB signaling. Mice supplemented with ω-3s, compared to mice on a control diet, expressed greater levels of CB1 and CB2 mRNA.

n summary, dietary ω-3s seem to act as homeostatic regulators of the eCB system. In obese rodents fed a high-AA diet, ω-3s significantly decrease eCBs, especially 2-AG, particularly in tissues that become dysregulated, such as adipose and liver tissues. Plasma eCB levels are reduced by krill oil also in obese humans. Little change in eCB levels are seen in normo-weight individuals not fed a high ω-6 diet, and dietary ω-3s are required for proper eCB signaling.

Human intestinal epithelial cells incubated with L. acidophilus produced more CB2 mRNA [145]. Feeding L. acidophilus to mice and rats increased the expression of CB2 mRNA in colonic epithelial cells. Lastly, mice fed L. acidophilus showed less pain behavior following colonic distension with butyrate than control mice, an effect reversed by the CB2 antagonist AM630[145].

Chronic or repeated stress results in a chronic elevation of endogenous corticosterone via the hypothalamic-pituitary-adrenocortical (HPA) axis. Chronic stress (repeated restraint) reduced AEA levels throughout the corticolimbic stress circuit in rodents [99][196][197].

In summary, chronic stress impairs the eCB system, via decreased levels of AEA and 2-AG. Changes in CB1 expression are more labile. Stress management may reverse the effects of chronic stress on eCB signaling, although few studies exploring this possibility have been performed to date. Clinical anecdotes suggests that stress-reduction techniques, such as meditation, yoga, and deep breathing exercises impart mild cannabimimetic effects [218].

Massage and osteopathic manipulation of asymptomatic participants increased serum AEA 168% over pretreatment levels; mean OEA levels decreased 27%, and no changes occurred in 2-AG. Participants receiving sham manipulation showed no changes [218].

Upregulation of the eCB system in obese humans seems to be driven by excessive production of eCBs in several peripheral tissues such as visceral adipose tissue, liver, pancreas, and skeletal muscle.

In summary, increased food intake, adiposity, and elevated levels of AEA and 2-AG apparently spiral in a feed-forward mechanism. Weight loss from caloric restriction breaks the cycle, possibly by reducing CB1 expression and reducing eCB levels.

Although both types of exercise regimens increased eCB ligand concentrations, only long-term-forced exercise led to sustained elevations of eCBs, and predictable CB1 downregulation.

In whole animals, however, caffeine’s effects are biphasic and vary by dosage and acute versus chronic administration. In humans, the acute administration of caffeine decreases headache pain, but exposure to chronic high doses, ≥300 mg/day, may exacerbate chronic pain [275].