Capsaicin, the primary pungent component of hot peppers, produced chemogenic and thermal antinociception within two hours after administration to adult guinea pigs (2-8 mg/kg). Antinociception lasted in excess of 10 days. In addition, in somewhat higher doses (4-25 mg/kg s.c.) capsaicin also depleted the putative peptide neurotransmitter, substance P, from primary afferent neurons. Depletion of substance P by capsaicin did not occur until at least one day after capsaicin treatment and the onset of antinociception. Antinociception produced by capsaicin appeared to be a result of bioactivation and covalent binding of capsaicin to the distal ends of sensory neurons. Capsaicin depleted substance P from sensory nerves by inhibiting the rate of substance P synthesis by 48 percent. Inhibition of substance P synthesis by capsaicin occurred with some degree of specificity as the rate at which total protein was synthesized was unchanged. The biochemical mechanism by which capsaicin altered substance P synthesis involved alterations in the retrograde axoplasmic transport of nerve growth factor. Doses of capsaicin which depleted substance P also inhibited the retrograde axoplasmic transport of nerve growth factor. Inhibition of the retrograde transport of nerve growth factor by capsaicin preceded substance P depletion. Supplementation of guinea pigs with mouse nerve growth factor completely prevented capsaicin-induced substance P depletion. It is concluded that capsaicin depletes substance P from primary afferent neurons of the adult guinea pig by altering the availability of NGF. The data support a role for NGF in the normal maintenance of neuropeptide levels in some sensory neurons in the adult animal.

No description available.

Thesis (M. Sc.)--University of Adelaide. / Includes bibliographical references (leaves 152-170).

Zugl.: Heidelberg, Univ., Diss., 2006 / Hergestellt on demand

Expt. 1 evaluated effects of 0 or 10 ppm CAP in the starter phase (d 1-16) on chicks challenged with SE on d of age. Therapeutic inclusion of 10ppm CAP increased (P < 0.05) L/S and ceca positives. In Expt. 2, capsaicin oleoresin (CO) was included in finisher diets (d 30-37) at 0, 5, or 20 ppm with SE challenge on day 31. Inclusion of 5 ppm CO increased (P < 0.05) ceca SE positives and demonstrated 1.05 and 1.39-log fewer SE cfu at CO concentration of 5 or 20 ppm, respectively. A linear decrease (P < 0.05) in lamina propria thickness of SE challenged birds was observed with increased CO. Expt. 3 evaluated prophylactic CO treatment at 0, 5, or 20 ppm in starter, grower, and finisher diets for resistance to SE or ST challenge on d 14 or 29. With challenge on d 14, 5 ppm CO reduced ceca (P<0.005) SE positives and 1.1-log fewer SE cfu. Likewise, 20 ppm CO reduced (P < 0.05) SE ceca positives. Salmonella typhimurium isolation rate was reduced (P<0.05) with 5 ppm CO, and ST cfu were reduced 1.4-log with 5 ppm CO compared to 20 ppm. Lamina propria thickness increased (P < 0.05) linearly as CO concentration increased. With d 29 challenge birds fed 5 ppm CO exhibited 1.08-log fewer SE cfu, and 20 ppm CO reduced L/S positives (P < 0.025) for SE and resulted in 1.39-log fewer SE cfu. Lamina propria thickness decreased with 5 ppm CO and SE or ST challenge compared to non-challenged birds fed 5 ppm (P < 0.0005). An increase was observed in ST or SE, birds fed 20 ppm CO compared to non-challenged, birds fed 20 ppm CO (P < 0.01). No differences were observed in mast cell number in either Expt. 2 or 3. These data provide evidence that prophylactic or therapeutic dietary CAP differentially affect broiler susceptibility to Salmonella and prophylactic administration may provide non-antibiotic means to reduce Salmonella in broilers. / Master of Science

Airway hyperresponsivness (AHR) is one of most prominent pathophysiological features of asthma. Increasing evidence suggests that vagal bronchopulmonary afferents may be involved in the development of AHR. However, the underlying mechanisms are not clear. Therefore, the purpose of this dissertation was to investigate the effect of chronic airway inflammation induced by allergen sensitization on vagal bronchopulmonary afferents. The study was carried out in an animal model of allergic asthma. Brown-Norway rats were sensitized by intraperitoneal Ovalbumin (Ova) and exposed to aerosolized Ova 3 times/week for three weeks. Control rats received the vehicle. In vivo single-fiber recording technique was applied in this study. Our results showed that chronic Ova exposure caused an elevated baseline activity of pulmonary Cfibers, and a distinctly higher sensitivity of these afferents to chemical stimulants and lung inflation. After an acute Ova inhalation challenge, the increase in baseline activity and the excitability of pulmonary C-fibers were further augmented in sensitized rats, but not in control rats. In addition, sensitivity of pulmonary myelinated afferents to capsaicin was significantly elevated after chronic airway inflammation was induced by allergen. Furthermore, immunohistochemsitry data showed that, in nodose ganglia the proportion of transient receptor potential vanilloids type 1 channels (TRPV1)-expressing bronchopulmonary neurons was significantly higher in sensitized rats than in controls. This increase of TRPV1 expression was found mainly in neurofilament-positive neurons (myelinated neurons), but this effect was absent in jugular ganglia. In conclusion, allergen-induced airway inflammation caused a pronounced sensitizing effect on vagal pulmonary non-myelinated (C-fiber) afferents and elevated the sensitivity of vagal pulmonary myelinated afferents to capsaicin. The latter was accompanied by the upregulation of TRPV1 expression in these myelinated neurons.

The effects of capsaicin, the major pungent component of hot peppers, were assessed on neuropeptide levels and on sensory function in neonatal and adult rats and in adult guinea pigs. Systemic doses of capsaicin in rats treated while neonates or while adults produced marked depletion of substance P (SP) in dorsal roots plus ganglia (DRG) and in dorsal spinal cord without altering tail-flick latencies in the treated animals. Guinea pigs had several-fold higher levels of SP than did rats in DRG and dorsal cord. In adult guinea pigs, systemic doses of capsaicin as low as 2.5 mg/kg depleted SP in DRG while a 10 mg/kg dose depleted the peptide maximally in DRG (85% decrease) and in the dorsal cord (35% decrease). High doses of capsaicin in guinea pigs had no consistent effects on levels of radioimmunoassayable cholecystokinin (CCK), vasoactive intestinal polypeptide, or somatostatin although a transient decrease in CCK levels was observed four days after dosing in DRG and in ventral cord. A single 5 mg/kg dose of capsaicin rendered animals completely insensitive to chemical irritation of the cornea without affecting sensitivity to noxious heat. Higher doses of capsaicin produced a marked insensitivity to nociceptive and non-nociceptive heat as well as to chemical irritation without affecting other sensory modalities. The SP depletion and sensory deficits produced by a single 50 mg/kg dose of capsaicin were still evident ten weeks later. The pattern of selectivity of the sensory deficits produced by capsaicin differed from that produced by morphine which was active against all forms of nociceptive stimuli. High doses of capsaicin also induced skin lesions and corneal opacities in guinea pigs. The syndrome of sensory effects produced by capsaicin in guinea pigs closely resembles the pattern of sensory deficits in familial dysautonomia, an autosomal recessive disorder in which there is a disappearance of SP from the substantia gelatinosa of the spinal cord. The results indicate that in the guinea pig capsaicin is potent at producing a unique, long-lasting syndrome of peripheral sensory deficits that may result from an action of the compound on SP-containing primary afferent neurons. Capsaicin is a valuable pharmacological tool for investigation of the neurochemistry and neurophysiology of primary afferent neurons and animals treated with the agent may be useful laboratory models of some forms of peripheral neuropathy.

Thesis (M.S.)--University of Akron, 2004. / Title from Web page (viewed on Dec. 17, 2007). "December, 2004." Includes bibliographical references (p. 118-124).

¡iAbstract¡j Neurogenic inflammation can be initiated by activation of sensory nerves to release neuropeptides, including tachykinins and calcitonin gene-related peptide. Capsaicin stimulation induces the release of substance P, the most important tachykinin and other neurotransmitters from sensory nerves to cause an increase of plasma leakage via the binding of substance P to NK1 receptors on endothelial cells. It has been proven that hyperthermic pretreatment decreases microvascular protein leakage and attenuates hypotension in anaphylactic shock in rats. Heat shock proteins¡]HSPs¡^are families of phylogenetically conserved molecules that have a protective role in all living cells under stress . Heat shock proteins are induced by whole-body hyperthermia and persist for 6 days. To establish the relationship between heat shock and neurogenic inflammation, the present study investigated whether whole-body hyperthermia pretreatment, at 42 ¢J for 15 min in rats 1 day earlier, could suppress inflammatory response in the lower airways and esophagus evoked by capsaicin (90 &#x00B5;g/ml/kg) or substance P (3 &#x00B5;g/ml/kg ). The magnitude of neurogenic inflammation in the trachea and bronchi was expressed by the area density of India ink-labeled leaky blood vessels in the airway mucosa. One day after heat shock pretreatment, capsaicin-evoked inflammation was reduced by one half to two thirds, and reduced substance P-evoked inflammation by one third. Six days after exposure to heat shock, neurogenic inflammation was not inhibited. HSPs appeared overexpressed in trachea and esophagus tissue in the rats one day after hyperthermia, but was less expressed 6 days after hyperthermia. It is suggested that exposure of the rats to whole-body hyperthermia caused an increased production of HSPs that might influence the affinity of the binding of substance P to NK1 receptors on venule endothelial cells, and reduce the amount of neurogenic plasma leakage.

Sustained gastroesophageal reflux (GER) causes airway inflammation and can be considered as a potential trigger of asthma. There are complex neural innervations and reflex mechanisms between trachea and esophagus, and close proximity between them also provide a chance that trachea and esophagus could heavily interact with each other. The studies of the interactions between trachea and esophagus began early, but how gastric contents in the esophagus cause airway inflammation are still not completely understood. In this study, we will observe the extent of airway inflammatory response of the Long Evans rats induced by intraesophageal infusion of different inflammatory agents. We simulated the condition of inflammatory substances in the esophagus by intraesophageal infusion of either capsaicin or 6-hydroxydopamine (6-OHDA). At the different time point after infusion of inflammatory substances, rats were sacrificed for the analysis of the amount of the plasma leakage in the lower airways and esophagus. The amount of plasma leakage was expressed by the area density of India ink-labeled leaky blood vessels in tissue whole mounts. From the previous studies, we realize that neural reflexes played an important role in GER-induced airway inflammation. In this research, we further studied whether vagus nerves were involved in this neural reflex pathway by the pretreatment of bilateral vagotomy. Free radicals generated by the oxidation of 6-OHDA and capsaicin damage the airway epithelium, and lead to the liberation of cellular contents and cytokines that will augment the inflammatory response. Free radicals also activate NF-£eB pathway and will further enhance the inflammatory response. We evaluate the extent of these free radicals involved in GER-induced airway inflammation, by pretreatment with a hydroxyl radical scavenger -dimethylthiourea (DMTU). Our results showed that plasma leakage in the airway increased time-dependently from 5 to 15 min after the infusion of 5 £gg/ml/kg of capsaicin. This response peaked at 15 min, and gradually diminished after 30 min of capsaicin application. Plasma leakage in the airways caused by the application of 10 mg/ml/kg of 6-OHDA also increased time-dependently and peaked at 30 min. We also demonstrated that the vagus nerve played an important role in GER-induced airway inflammation. Because bilateral vagotomy significantly alleviated the airway inflammatory response caused by the application of capsaicin. Free radicals also involved in this process, because pretreatment with (2.25 g/kg, i.v.) DMTU significantly lowered the amount of plasma leakage caused by capsaicin and 6-OHDA.