371 Selective inhibitory effect of 5-hydroxymethyl tolterodine (5-HMT), an active metabolite of fesoterodine, on capsaicin-sensitive C-fibers among the primary bladder mechanosensitive afferent nerves in the rat

Activation of the vagal afferents by noxious gastrointestinal stimuli suggests that vagal afferents may play a complex role in visceral pain processes. The contribution of the vagus nerve to visceral pain remains unresolved. Previous studies reported that patients following chronic vagotomy have lower pain thresholds. The patient with irritable bowel syndrome has been shown alteration of vagal function. We hypothesize that vagal afferent nerves modulate visceral pain. Visceromotor responses (VMR) to graded colorectal distension (CRD) were recorded from the abdominal muscles in conscious rats. Chronic subdiaphragmatic vagus nerve sections induced 470, 106, 51, and 54% increases in VMR to CRD at 20, 40, 60 and 80 mmHg, respectively. Similarly, at light level of anesthesia, topical application of lidocaine to the subdiaphragmatic vagus nerve in rats increased VMR to CRD. Vagal afferent neuronal responses to low or high-intensity electrical vagal stimulation (EVS) of vagal afferent Aδ or C fibers were distinguished by calculating their conduction velocity. Low-intensity EVS of Aδ fibers (40 μA, 20 Hz, 0.5 ms for 30 s) reduced VMR to CRD at 40, 60, and 80 mmHg by 41, 52, and 58%, respectively. In contrast, high-intensity EVS of C fibers (400 μA, 1 Hz, 0.5 ms for 30 s) had no effect on VMR to CRD. In conclusion, we demonstrated that vagal afferent nerves modulate visceral pain. Low-intensity EVS that activates vagal afferent Aδ fibers reduced visceral pain. Thus EVS may potentially have a role in the treatment of chronic visceral pain.

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Inhibitory effect of amiloride and gadolinium on fine afferent nerves in the rat knee: evidence of mechanogated ion channels in joints

Experimental Brain Research ◽

10.1007/s00221-005-0040-z ◽

2005 ◽

Vol 167 (1) ◽

pp. 114-118 ◽

Cited By ~ 21

Author(s):

Bernd Heppelmann ◽

Jason J. McDougall

Keyword(s):

Ion Channels ◽

Inhibitory Effect ◽

Afferent Nerves

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Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00862.2005 ◽

2006 ◽

Vol 291 (2) ◽

pp. R454-R463 ◽

Cited By ~ 61

Author(s):

Brendan J. Canning ◽

David G. Farmer ◽

Nanako Mori

Keyword(s):

Citric Acid ◽

Guinea Pigs ◽

Transient Receptor Potential ◽

Superior Laryngeal Nerve ◽

Transient Receptor Potential Vanilloid ◽

Receptor Antagonists ◽

Tracheal Mucosa ◽

C Fibers ◽

Afferent Nerves ◽

Vagal Afferent

Experiments carried out in conscious guinea pigs suggest that citric acid-evoked coughing is partly mediated by transient receptor potential vanilloid type 1 (TRPV1) receptor-dependent activation of tachykinin-containing, capsaicin-sensitive C fibers. In vitro electrophysiological analyses indicate, however, that acid also activates capsaicin-sensitive and -insensitive vagal afferent nerves by a TRPV1-independent mechanism, and studies in anesthetized guinea pigs show that coughing evoked by acid is mediated by activation of capsaicin-insensitive vagal afferent nerves. In the present study, we have characterized the mechanisms of citric acid-evoked coughing in anesthetized guinea pigs. Drugs were administered directly to the Krebs buffer perfusing the extrathoracic trachea. Citric acid was applied topically to the tracheal mucosa, directly into the tracheal perfusate in increasing concentrations and at 1-min intervals. Citric acid dose dependently evoked coughing in anesthetized guinea pigs. This was mimicked by hydrochloric acid but not by sodium citrate. The coughing evoked by acid was nearly or completely abolished by TTX or by cutting the recurrent laryngeal nerves. Perfusing the trachea with a low Cl− buffer potentiated the acid-induced cough reflex. In contrast, prior capsaicin desensitization, 10 μM capsazepine, Ca2+-free perfusate, 0.1 μM iberiotoxin, 1 μM atropine, 10 μM isoproterenol, 10 μM albuterol, 3 μM indomethacin, 0.1 μM HOE-140, a combination of neurokinin1 (NK1; CP-99994), NK2 (SR-48968), and NK3 (SB-223412) receptor antagonists (0.1 μM each), a combination of histamine H1 (3 μM pyrilamine) and cysLT1 (1 μM ICI-198615) receptor antagonists, superior laryngeal nerve transection, or epithelium removal did not inhibit citric acid-evoked coughing. These and other data indicate that citric acid-evoked coughing in anesthetized guinea pigs is mediated by direct activation of capsaicin-insensitive vagal afferent nerves, perhaps through sequential activation of acid-sensing ion channels and chloride channels.

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Inhibitory effect of penciclovir, the active metabolite of famciclovir, on the priming of hepadnavirus reverse transcription

Hepatology ◽

10.1016/0270-9139(95)95038-9 ◽

1995 ◽

Vol 22 (4) ◽

pp. A329 ◽

Cited By ~ 2

Author(s):

F ZOULIM

Keyword(s):

Reverse Transcription ◽

Active Metabolite ◽

Inhibitory Effect

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Differential effects of airway afferent nerve subtypes on cough and respiration in anesthetized guinea pigs

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90382.2008 ◽

2008 ◽

Vol 295 (5) ◽

pp. R1572-R1584 ◽

Cited By ~ 61

Author(s):

Yang-Ling Chou ◽

Mark D. Scarupa ◽

Nanako Mori ◽

Brendan J. Canning

Keyword(s):

Citric Acid ◽

Hypertonic Saline ◽

Guinea Pigs ◽

Afferent Nerve ◽

Vagal Afferents ◽

C Fibers ◽

Afferent Nerves ◽

Nodose Ganglia ◽

Opposing Effects ◽

Respiratory Reflexes

The hypothesis that respiratory reflexes, such as cough, reflect the net and often opposing effects of activation of multiple afferent nerve subpopulations throughout the airways was evaluated. Laryngeal and tracheal mucosal challenge with either citric acid or mechanical probing reliably evoked coughing in anesthetized guinea pigs. No other stimulus reliably evoked coughing in these animals, regardless of route of administration and despite some profound effects on respiration. Selectively activating vagal C-fibers arising from the nodose ganglia with either adenosine or 2-methyl-5-HT evoked only tachypnea. Selectively activating vagal afferents arising from the jugular ganglia induced respiratory slowing and apnea. Nasal afferent nerve activation by capsaicin, citric acid, hypertonic saline, or histamine evoked only respiratory slowing. Histamine, which activates intrapulmonary rapidly adapting receptors but not airway or lung C-fibers or tracheal bronchial cough receptors induced bronchospasm and tachypnea, but no coughing. The results indicate that the reflexes initiated by stimuli thought to be selective for some afferent nerve subtypes will likely depend on the net and potentially opposing effects of multiple afferent nerve subpopulations throughout the airways. The data also provide further evidence that the afferent nerves regulating cough in anesthetized guinea pigs are distinct from either C-fibers or intrapulmonary rapidly adapting receptors.

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Inhibitory effects on intake of cholecystokinin-8 and cholecystokinin-33 in rats with hepatic proper or common hepatic branch vagal innervation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00062.2005 ◽

2005 ◽

Vol 289 (2) ◽

pp. R456-R462 ◽

Cited By ~ 23

Author(s):

S. Eisen ◽

R. J. Phillips ◽

N. Geary ◽

E. A. Baronowsky ◽

T. L. Powley ◽

...

Keyword(s):

Intraperitoneal Administration ◽

Inhibitory Effect ◽

Inhibitory Interaction ◽

Afferent Nerves ◽

Afferent Fibers ◽

Vagal Nerves ◽

Vagal Innervation ◽

Afferent Vagal ◽

Vagal Afferent ◽

Hepatic Branch

The relative potencies of cholecystokinin (CCK)-8 and CCK-33 for decreasing meal size depend on the route of administration. Inhibitory potencies are equal after intraperitoneal administration, but CCK-33 is significantly more potent after intraportal administration. This suggests that CCK-33 is a more effective stimulant of hepatic afferent vagal nerves than is CCK-8. To investigate this possibility, we administered both peptides intraperitoneally in rats with abdominal vagotomies that spared only the hepatic proper vagal nerves (H) and in rats with abdominal vagotomies that spared the common hepatic branch that contains the fibers of the hepatic proper and gastroduodenal nerves (HGD). The vagal afferent innervation in H and HGD rats was verified with a wheat germ agglutinin-horseradish tracer strategy. Intraperitoneal administration of CCK-33 decreased 30-min intake of 10% sucrose in H rats as much as in sham rats, but CCK-8 decreased intake significantly less in H rats than in sham rats. The larger inhibitory effect of CCK-33 than of CCK-8 in H rats is consistent with the hypothesis that CCK-33 is a more effective stimulant of the hepatic proper vagal afferent nerves than CCK-8. In contrast to the results in H rats, the inhibitory potencies of both peptides were significantly and equivalently reduced in HGD rats compared with sham rats. This suggests that there is an inhibitory interaction between the stimulation of the gastroduodenal and hepatic proper afferent fibers by CCK-33.

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