Role Of Capsaicin-sensitive Sensory Neurons Research Articles

The role of capsaicin-sensitive sensory neurons in autonomic dysreflexia in the spinal cord injured-rat

Background: A subpopulation of sensory neurons express the transient receptor potential cation channel subfamily V member 1 (TRPV1). It is activated by heat (>43°C), low pH, and capsaicin (the pungent ingredient in hot chili peppers), and has emerged as a promising target for the treatment of pain. Both pain and autonomic dysreflexia that develop in the wake of SCI have been attributed to maladaptive sensory plasticity. We hypothesize that TRPV-1-positive afferents contribute to the development of autonomic dysreflexia (AD).

Impaired Basal Thermal Homeostasis in Rats Lacking Capsaicin-sensitive Peripheral Small Sensory Neurons

We studied the effects of selective loss of capsaicin-sensitive primary sensory neurons on thermosensation and thermoregulation in rats. Neonatal capsaicin treatment in rats caused a remarkable decrease in the number of small-diameter neurons in the dorsal root ganglion (DRG) compared with their number in the control rats. Gene expression analysis for various thermo-sensitive transient receptor potential (TRP) channels indicated marked reductions in the mRNA levels of TRPV1 (70%), TRPM8 (46%) and TRPA1 (64%), but not of TRPV2, in the DRG of capsaicin-treated rats compared with those in the control rats. In addition to the heat and cold insensitivity, capsaicin-treated rats showed lower rectal core temperature, higher skin temperature and decreased sensitivity to ambient temperature alteration under normal housing at room temperature, suggesting impaired thermosensation and change in thermoregulation in the rats. Uncoupling protein 1 (UCP1) expression and the thermogenic ability in brown adipose tissues were attenuated in the capsaicin-treated rats. These results indicate a critical role of capsaicin-sensitive sensory neurons in both heat and cool sensation and hence in basal thermal homeostasis, which is balanced by heat release and production including UCP1 thermogenesis, following sensation of the ambient temperature.

Role of capsaicin-sensitive sensory nerves in protease-activated receptor-2-mediated contraction of rat urinary bladder

The capsaicin receptor, transient receptor potential vanilloid receptor 1 (TRPV1), colocalizes with protease-activated receptors (PARs) in the urinary bladder, but functional interaction between TRPV1 and PARs remains to be clarified. In the present study, the role of capsaicin-sensitive sensory neurons in contraction induced by activation of PAR-2 was investigated in the rat urinary bladders. The contractile responses to trypsin and the PAR-2 agonist 2-furoyl-LIGRL-NH 2 were significantly attenuated by either desensitization of sensory neurons achieved by capsaicin (10 μM) or by the TRPV1 antagonist capsazepine (30 μM). These results suggest that stimulation of capsaicin-sensitive sensory fibers contributes, at least in part, to PAR-2-mediated bladder contractions in rats.

Critical role of capsaicin-sensitive sensory neurons in gender difference in the stress-induced gastric mucosal injury in rats

Recent studies have demonstrated that the outcome of critically ill patients is better in females than in males. Although estrogen has been shown to be critically involved in regulation of immune responses, the detailed mechanism(s) underlying such gender differences has yet to be fully understood. Since proinflammation plays a critical role in the development of the organ dysfunction seen in such critically ill patients, estrogen might show any anti-inflammatory effects to attenuate such inflammatory responses. We previously reported that capsaicin-sensitive sensory neurons (CSSN), nociceptive neurons, play an important role in attenuating inflammatory responses by releasing calcitonin gene-related peptide (CGRP), which promotes the endothelial production of prostacyclin, one of the anti-inflammatory prostaglandins [1]. Since estrogen increases the synthesis of nerve growth factor, which increases the CGRP production, estrogen might attenuate inflammatory responses by promoting CGRP release from CSSN. We examined this possibility in the present study.

Increased susceptibility of gastric mucosa to ulcerogenic stimulation in diabetic rats--role of capsaicin-sensitive sensory neurons.

1. We examined the gastric mucosal blood flow (GMBF) and ulcerogenic responses following barrier disruption induced by sodium taurocholate (TC) in diabetic rats and investigated the role of capsaicin-sensitive sensory neurons in these responses. 2. Animals were injected streptozotocin (STZ: 70 mg kg(-1), i.p.) and used after 5, 10 and 15 weeks of diabetes with blood glucose levels of > 350 mg dl(-1). The stomach was mounted on an ex-vivo chamber under urethane anaesthesia and exposed to 20 mM TC plus 50 mM HCl for 30 min in the presence of omeprazole. Gastric transmucosal potential difference (PD), GMBF, and luminal acid loss (H+ back-diffusion) were measured before and after exposure to 20 mM TC, and the mucosa was examined for lesions 90 min after TC treatment. 3. Mucosal application of TC caused PD reduction in all groups; the degree of PD reduction was similar between normal and diabetic rats, although basal PD values were lower in diabetic rats. In normal rats, TC treatment caused luminal acid loss, followed by an increase of GMBF, resulting in minimal damage in the mucosa. 4. The increased GMBF responses associated with H+ back-diffusion were mitigated in STZ-treated rats, depending on the duration of diabetes, and severe haemorrhagic lesions occurred in the stomach after 10 weeks of diabetes. 5. Intragastric application of capsaicin increased GMBF in normal rats, but such responses were mitigated in STZ diabetic rats. The amount of CGRP released in the isolated stomach in response to capsaicin was significantly lower in diabetic rats when compared to controls. 6. The deleterious influences on GMBF and mucosal ulcerogenic responses in STZ-diabetic rats were partially but significantly antagonized by daily insulin (4 units rat(-1)) treatment. 7. These results suggest that the gastric mucosa of diabetic rats is more vulnerable to acid injury following barrier disruption, and this change is insulin-sensitive and may be partly accounted for by the impairment of GMBF response associated with acid back-diffusion and mediated by capsaicin-sensitive sensory neurons.

Role of Capsaicin-Sensitive Sensory Neurons and Nitric Oxide in the Protective Effect of Lansoprazole, a Proton Pump Inhibitor, on the Gastric Mucosa in Rats

The mucosal protective effect of lansoprazole, a proton pump inhibitor, was examined in ethanol- and acidified taurocholate-induced rat gastric lesion models. The formation of gastric lesions was markedly inhibited by prostaglandin E2 but hardly inhibited by cimetidine, ranitidine and famotidine. Lansoprazole (3–30 mg/kg, p.o.) inhibited the formation of gastric lesions in a dose-dependent manner, with ID50 values of 8.5 (ethanol) and 4.1 mg/kg, p.o. (acidified taurocholate). The protective effect of lansoprazole was significantly decreased by functional ablation of capsaicin-sensitive sensory neurons or prior administration of indomethacin or Nω-nitro-L-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide (NO) synthesis. The inhibitory effect of L-NAME was antagonized by prior administration of L-arginine, a substrate of endogenous NO, but not D-arginine. The antisecretory effect of lansoprazole on the basal acid secretion in pylorus-ligated rats was not affected by any of these treatments. Lansoprazole (5 and 15 mg/ml) administered directly into the gastric chamber obviously increased both the production of NO in the mucosa and mucosal blood flow, which was prevented by pretreatment with L-NAME. These results suggest that capsaicin-sensitive sensory neurons, NO and prostaglandins are involved in the mucosal protection afforded by lansoprazole possibly via an increase in mucosal blood flow, but are not involved in the antisecretory action of lansoprazole.

The role of capsaicin-sensitive sensory neurons and nitric oxide in regulation of gastric mucosal growth: [formula omitted], Z. Warzecha, P. Ceranowicz S.J. Konturek. Inst. Physiol. Univ. Sch. Med., Krakow, Poland

Capsaicin and nitric oxide (NO) cause potent vasorelaxation which is important in gastroprotective activity against damage but the mechanisms underlying these effects have not been elucidated. This study investigated the influence of capsaicin-induced functional ablation of afferent neurons and inhibition of NO production on the gastric mucosal growth in normal conditions, after 48 h fasting and subsequent refeeding. We found that ablation of sensory neurons by capsaicin pretreatment (100 mg/kg over 3 days) reduced by around 45% the mucosal blood flow (MBF), as measured by laser Doppler flowmetry, in normal fed and refed rats, while by 15% only in fasted animals. This last group of animals had significant decrease in the MBF even in control conditions as compared to that recorded in fed animals. This drop in MBF after capsaicin-induced denervation was accompanied by a significant decrease in DNA synthesis (by 40% in control group and 35% in refed rats) and was less pronounced in the group of fasted rats (23%). Ablation of sensory neurons resulted in the decrease in the stomach weight and RNA content in regular feed and refed but not in 48 h fasted group of animals. Treatment with NG-nitro-L-arginine (L-NNA; 2 x 20 mg/kg daily s.c.), a selective blocker of NO synthase, significantly suppressed the MBF in all three groups of animals tested but this suppression was less pronounced when compared to capsaicin pretreatment. This inhibitory effect of L-NNA on MBF was fully antagonized by L-arginine (2 x 100 mg/kg daily s.c.). L-NNA injection s.c. reduced the DNA synthesis (36% control group, 38% refed animals, 18% fasted rats), stomach weight, RNA and DNA content in all tested groups of rats. This inhibition was reversed by the addition of L-arginine. The combination of capsaicin and L-NNA decreased the MBF significantly and the inhibition was stronger than the effect of each substance given alone. In normal fed and refed rats, the neurotoxic dose of capsaicin together with L-NNA significantly decreased the DNA synthesis, stomach weight, RNA and DNA content but these effects were smaller than the sum of the effects of each agent given alone. We conclude that both the capsaicin-induced denervation and the suppression of endogenous NO by L-NNA inhibit the growth of the gastric mucosa by the mechanism involving, at least in part, the suppression of gastric mucosal blood flow.

Neonatal capsaicin treatment does not prevent splanchnic vasodilatation in portal-hypertensive rats.

It has been suggested that the peripheral sensory neurons are involved in the splanchnic hemodynamic changes of portal hypertension. Therefore the influence of permanent ablation of sensory neurons by neonatal capsaicin pretreatment (50 mg/kg, subcutaneously) on the development of the hyperdynamic splanchnic circulation in portal-hypertensive rats was studied. In adulthood, portal hypertension was induced with partial portal vein ligation. In study 1, systemic and splanchnic hemodynamics were measured by means of a radiolabeled-microsphere technique in portal-hypertensive rats, under ketamine anesthesia, pretreated with capsaicin or vehicle. Mean arterial pressure, heart rate, cardiac index, systemic and splanchnic vascular resistance, portal pressure, portal venous inflow, portal-collateral resistance and portal-systemic shunting were not significantly different between capsaicin-pretreated and vehicle-pretreated rats. In study 2, gastric mucosal blood flow, measured by means of hydrogen gas clearance, and the hemoglobin and oxygen content of the gastric mucosa, as assessed with reflectance spectrophotometry, were not significantly different in the two groups of anesthetized portal-hypertensive rats pretreated with capsaicin or vehicle. In study 3, we confirmed the effectiveness of neonatal capsaicin pretreatment by measuring calcitonin gene-related peptide content of the gastric corpus wall. Capsaicin pretreatment caused a depletion of calcitonin gene-related peptide by at least 98% compared with that in vehicle-pretreated rats. These results do not support a role of capsaicin-sensitive sensory neurons that innervate the gastrointestinal tract in the development of the splanchnic vasodilatation characteristically observed in chronic portal hypertension.

Capsaicin-sensitive sensory neurons in healing gastric lesions induced by HCl in rats.

The role of capsaicin-sensitive sensory neurons in the healing of HCl-induced gastric lesions was investigated in rats. Rats fasted for 18 hr were given 0.6 N HCl orally for induction of gastric lesions, and they were fed normally from 1 hr later. On various days after HCl treatment, area of lesions, acid secretion, mucosal H+ permeability, and blood flow responses were measured. Functional ablation of capsaicin-sensitive sensory neurons was performed two weeks before the experiment by subcutaneous injections of high-dose capsaicin. Sensory deafferentation did not affect the development of gastric damage in response to HCl but significantly delayed the healing of these lesions. The mucosa damaged by HCl secreted less acid but showed significant rise in H+ permeability, resulting in acid back-diffusion accompanied by an increase of mucosal blood flow. Sensory deafferentation had no effect on acid secretion and mucosal permeability changes in the damaged stomach but completely blocked the hyperemic response caused by acid back-diffusion. Capsaicin-sensitive sensory neurons may contribute to healing of gastric lesions, probably by mediating the mucosal hyperemic responses associated with acid back-diffusion and by facilitating acid disposal in the mucosa.

The role of capsaicin-sensitive sensory neurons in healing of HCl-lnduced gastric mucosal lesions in rats

Background/Aims: Capsaicin-sensitive sensory neurons are important in protecting the stomach against damage. This study investigated the role of these sensory neurons in the healing of gastric lesions. Methods: Rats fasted for 18 hours were given 1 ml of 0.6N HCI orally for induction of gastric lesions; they were then fed normally from 1 hour later. On various days after HCI treatment, the area of lesion, acid secretion, mucosal DNA synthesis, mucosal H+ permeability, and blood flow responses were measured. Results: Ablation of sensory neurons by capsaicin pretreatment did not affect the development of gastric lesions in response to HCI but significantly delayed the healing of these lesions. The damaged mucosa secreted less acid and had minimal changes in DNA synthesis but showed a marked increase in H+ permeability, resulting in luminal acid loss accompanied by an increase of mucosal blood flow. Sensory deafferentation did not have any influence on such changes in the damaged stomach, except the mucosal hyperemic response to acid. Conclusions: Capsaicin-sensitive sensory neurons may contribute to the healing of gastric lesions by mediating the mucosal hyperemic responses associated with acid back-diffusion and by facilitating acid disposal in the mucosa.

Regulation of gastroduodenal bicarbonate secretion by capsaicin-sensitive sensory neurons in rats.

We investigated the role of capsaicin-sensitive sensory neurons in regulation of gastroduodenal HCO3- secretion in anesthetized rats. The stomach (under acid inhibition by omeprazole 60 mg/kg i.p.) or the duodenum was perfused with saline (pH 4.5) and HCO3- output was determined by pH change in the perfusate. Both the duodenum and stomach responded to prostaglandin E2 (PGE2; 300 micrograms/kg i.v.) or luminal acid by a significant increase in pH and HCO3- output. These tissues also responded to luminal application of capsaicin (0.3-6 mg/ml for 30 min), resulting in a significant increase of pH and HCO3- output in a concentration-related manner. The HCO3- stimulatory action of capsaicin was markedly attenuated by functional ablation of capsaicin-sensitive sensory neurons, significantly mitigated by indomethacin, and exhibited tachyphylaxis after repeated application at a high concentration. The acid-induced pH and HCO3- responses were also significantly mitigated by sensory deafferentation and by indomethacin, whereas those induced by PGE2 remained unaffected. In addition, defunctionalization of these sensory nerves resulted in macroscopically visible damage in the duodenum when acid secretion was concomitantly stimulated by histamine. We conclude that capsaicin-sensitive sensory neurons may be involved in the regulatory mechanism of gastroduodenal HCO3- secretion and contribute to protection of the mucosa against acid. Endogenous PGs may be involved in the HCO3- stimulatory action mediated by capsaicin-sensitive sensory neurons.