C-fiber Neurons Research Articles

Pathophysiology of the overactive bladder and its pharmacological treatment

This paper reviews the possible mechanisms underlying bladder overactivity and discusses the targets for pharmacological treatment of this disorder. Damage to the brain (cerebrovascular disease, etc.) induces bladder overactivity by reducing suprapontine inhibition. Currently, attention has focused on C-fiber bladder afferents that may concern the mechanisms for bladder overactivity resulting from various etiologies such as spinal cord lesions, bladder outlet obstruction and bladder hypersensitivity disorders. With regard to the pathophysiology of idiopathic overactive bladder, both myogenic and neurogenic mechanisms may be involved in involuntary detrusor contraction. Since an intravesical capsaicin or resiniferatoxin was shown to have favorable therapeutic effects, afferent C-fiber neurons become a new target for pharmacological treatment. C-fiber neurons are known to contain tachykinins and other peptides as neurotransmitters. When released, tachykinins can influence via NK receptors bladder activity. In addition, evidences suggest that ATP receptors (P2X3) and prostaglandin receptors in afferent C-fiber neurons may play a role in mediating bladder overactivity. Thus, NK-antagonist, P2X3-antagonist and PG receptor-antagonist may be potential therapeutic drugs in the near future. beta 3-Adrenoceptor agonist is an another candidate drug for the treatment of the overactive bladder. Finally, it is important to notice that in any etiology including an idiopathic one, antimuscarinic drugs can improve bladder overactivity, although dry mouth and constipation are inevitable side-effects.

Intravesical Resiniferatoxin For Refractory Detrusor Hyperreflexia: A Multicenter, Blinded, Randomized, Placebo-Controlled Trial

Objective: Resiniferatoxin (RTX) is an analogue of capsaicin with more than 1,000 times its potency in desensitizing C-fiber bladder afferent neurons. This study investigated the safety and efficacy of intravesical RTX in patients with refractory detrusor hyperreflexia (DH).Methods: Thirty-six (22 males, 14 females) neurologically impaired patients (20 spinal cord injury, 7 multiple sclerosis, 9 other neurologic diseases) with urodynamically verified DH and intractable urinary symptoms despite previous anticholinergic drug use were treated prospectively with intravesical RTX using dose escalation in a double-blind fashion at 4 centers. Patients received a single instillation of 100 ml of placebo (n = 8 patients) or 0.005, 0.025, 0.05 , 0.10 , 0.2, 0.5, or 1.0 fLM of RTX (n = 4 each group). A visual analog pain scale (VAPS) (0-10; 10 = highest level of pain) was used to quantify discomfort of application. Treatment effect was monitored using a bladder diary and cystometric bladder capacity at weeks 1, 3, 6, and 1 2 posttreatment.Results: Mean VAPS scores revealed minimal to mild discomfort with values of 2.85 and 2.28 for the 0.5-j-LM and 1.0-j-LM RTX treatment groups, respectively. Due to the small sample size, there were no statistically significant changes in mean cystometric capacity (MCC) or incontinence episodes in each treatment dose group. However, at 3 weeks, MCC increased by 53% and 48% for the 0.5-j-μM and 1.0-j-μM RTX treatment groups, respectively. Patients in the 0.5-j-μM and 1.0-j-μM groups with MCC < 300 ml at baseline showed greater improvements in MCC at 120.5% and 48%, respectively. In some patients, MCC increased up to 500% over baseline, despite a low RTX dose. Incontinence episodes decreased by 51.9% and 52.7% for the 0.5-j-LM and 1.0-j-LM RTX treatment groups, respectively. There were no long-term complications.Conclusion: Intravesical RTX administration, in general, is a well-tolerated new therapy for DH. This patient group was refractory to all previous oral pharmacologic therapy, yet some patients responded with significant improvement in bladder capacity and continence function shortly after RTX administration. Patients at risk for autonomic dysreflexia require careful monitoring during RTX therapy.

Allergic inflammation-induced neuropeptide production in rapidly adapting afferent nerves in guinea pig airways.

In the vagal-sensory system, neuropeptides such as substance P and calcitonin gene-related peptide (CGRP) are synthesized nearly exclusively in small-diameter nociceptive type C-fiber neurons. By definition, these neurons are designed to respond to noxious or tissue-damaging stimuli. A common feature of visceral inflammation is the elevation in production of sensory neuropeptides. Little is known, however, about the physiological characteristics of vagal sensory neurons induced by inflammation to produce substance P. In the present study, we show that allergic inflammation of guinea pig airways leads to the induction of substance P and CGRP production in large-diameter vagal sensory neurons. Electrophysiological and anatomical evidence reveals that the peripheral terminals of these neurons are low-threshold Adelta mechanosensors that are insensitive to nociceptive stimuli such as capsaicin and bradykinin. Thus inflammation causes a qualitative change in chemical coding of vagal primary afferent neurons. The results support the hypothesis that during an inflammatory reaction, sensory neuropeptide release from primary afferent nerve endings in the periphery and central nervous system does not require noxious or nociceptive stimuli but may also occur simply as a result of stimulation of low-threshold mechanosensors. This may contribute to the heightened reflex physiology and pain that often accompany inflammatory diseases.

Expression of capsaicin receptor (VR1) by myelinated primary afferent neurons in rats

The expression of capsaicin (VR1) receptor by A-fiber primary afferent neurons has been investigated by double immunohistochemical staining with VR1 and 200 kD neurofilament (NF200; an A-fiber marker) antibodies, and by VR1 immunohistochemical staining in combination with cholera toxin B subunit (CTB; also an A-fiber marker) retrograde tracing. Approximately 30% of the VR1-positive dorsal root ganglion (DRG) neurons were NF200-positive. Intra-sciatic nerve injection of CTB labeled over 30% of the VR1-positive neurons in the L5 DRG. Size frequency distribution analysis revealed that these VR1 and NF200, or VR1 and CTB, double-labeled neurons were predominantly small and medium sized. These results suggest that capsaicin receptors are likely to be expressed by Aδ-fiber neurons as well as C-fiber neurons.

Vanilloid receptor homologue, VRL1, is expressed by both A- and C-fiber sensory neurons.

The capsaicin receptor (VR1) homologue, VRL1, is thought to be responsible for transducing high-threshold heat responses in Adelta-fiber neurons. In the present study, the expression of VRL1 by A- or C-fiber sensory neurons in rats was investigated by using a VRL1 and 200 kDa neurofilament (NF200, an A-fiber marker) double immunohistochemical staining method. Approximately 46% of VRL-positive neurons were NF200 positive. Though double-labeled neurons tended to be medium to large, many VRL1 single-labeled neurons were large. Dense VRL1 immunoreactivity was also found in laminae I and II of the spinal dorsal horn, where nociceptive Adelta- and C-fibers normally terminate. These results suggest that both C-fiber and Adelta-fiber primary sensory neurons express VRL1, and VRL1 may play an important role in nociception.

Dermal neurovascular dysfunction in type 2 diabetes.

To review evidence for a relationship between dermal neurovascular dysfunction and other components of the metabolic syndrome of type 2 diabetes. We review and present data supporting concepts relating dermal neurovascular function to prediabetes and the metabolic syndrome. Skin blood flow can be easily measured by laser Doppler techniques. Heat and gravity have been shown to have specific neural, nitrergic, and independent mediators to regulate skin blood flow. We describe data showing that this new tool identifies dermal neurovascular dysfunction in the majority of type 2 diabetic patients. The defect in skin vasodilation is detectable before the development of diabetes and is partially correctable with insulin sensitizers. This defect is associated with C-fiber dysfunction (i.e., the dermal neurovascular unit) and coexists with variables of the insulin resistance syndrome. The defect most likely results from an imbalance among the endogenous vasodilator compound nitric oxide, the vasodilator neuropeptides substance P and calcitonin gene-related peptide, and the vasoconstrictors angiotensin II and endothelin. Hypertension per se increases skin vasodilation and does not impair the responses to gravity, which is opposite to that of diabetes, suggesting that the effects of diabetes override and counteract those of hypertension. These observations suggest that dermal neurovascular function is largely regulated by peripheral C-fiber neurons and that dysregulation may be a component of the metabolic syndrome associated with type 2 diabetes.

Evaluation of Capsaicin's Use in Analgesic Medicine

ABSTRACT Capsaicin, trans-methyl N-vanillyl-nonenamide, is the major pungent compound derived from the hot pepper plant. Regular and cumulative topical applications of capsaicin cream has been shown to produce analgesic effects in many painful medical conditions. This effect is mediated by a neuronal mechanism which involves the depletion of substance P from C-fiber sensory neurons. The elucidation of a receptor-mediated mechanism at the vanilloid receptor has further explained the biochemical events observed with capsaicin use. Use of capsaicin in the therapeutic setting is desirable due to its non-narcotic non-steroidal properties. Toxcity symptoms are evident only in large doses. This review includes research on capsaicin's use as an analgesic in three painful medical conditions: postherpetic neuralgia, osteoarthri-tis and postmastectomy pain syndrome. All report some degree of improvement in pain with capsacin use. Although only a small sample of medical conditions are represented here, a variety of o...

Intravesical neuromodulatory drugs: capsaicin and resiniferatoxin to treat the overactive bladder.

Current pharmacologic treatment of the overactive bladder relies on anticholinergic drugs. However, these drugs often have troublesome side effects and frequently are given in doses insufficient to restore continence in patients with detrusor instability. We present the background and basic and clinical research dealing with intravesical instillation of capsaicin and resinfferatoxin as treatments for the overactive bladder. Capsaicin is the main pungent ingredient in "hot" peppers of the genus Capsicum. It is a specific neurotoxin that desensitizes C-fiber afferent neurons, which may be responsible for the signals that trigger detrusor overactivity. Studies with capsaicin over the past 8 years have demonstrated clinical efficacy with minimal long-term complications. Most of these studies have also shown that the acute pain and irritation associated with capsaicin are a major deterrent to widespread use. Resiniferatoxin (RTX), an ultrapotent analog of capsaicin that appears to have similar efficacy but with much less acute side effects may be more useful. Intravesical instillation of capsaicin or resiniferatoxin is a promising treatment for the overactive bladder.

Primary nociceptive afferents mediate the blood flow dysfunction in non-glabrous (hairy) skin of type 2 diabetes: a new model for the pathogenesis of microvascular dysfunction.

To test the independent contributions of vascular endothelium, sympathetic activation and inhibition, vessel distensibility, and nociceptor-mediated vasodilation in both glabrous and hairy skin circulations. We measured blood flow using laser Doppler techniques in 10 people with type 2 diabetes and 10 age- and BMI-matched healthy control subjects at the pulp of the index finger (glabrous skin) and the dorsum of the hand (hairy skin). A 5-min ischemic block of the arm was used to test vascular endothelium. Warming of the probe site to 45 degrees C tested neurogenic vasodilation in hairy skin only. Vessel distensibility was tested by gravitational pressure. Basal blood flow and reactive hyperemia did not differ between groups at either skin site. The vasodilative response to local warming (P < 0.01) and limb lowering (P < 0.05) were significantly different between groups in hairy skin but not in glabrous skin in the absence of objective measured neuropathy. Nociceptor-mediated flow correlated significantly with the warm thermal threshold (r = -0.50, P < 0.05). Endothelial-mediated blood flow correlated with systolic blood pressure (r = -0.76, P < 0.01), LDL cholesterol (r = -0.62, P < 0.001), C-peptide (r = 0.65, P < 0.05), and triglycerides (r = 0.47, P < 0.05). These data suggest that neurogenic nociceptor-mediated vasodilation is impaired in subjects with type 2 diabetes when endothelial and sympathetic function are relatively intact. Heat-induced vasodilation may be a specific test of small heat-sensitive C-fiber peripheral neurons and may be an integral part of the metabolic syndrome.

Epidural resiniferatoxin induced prolonged regional analgesia to pain

Adequate treatment of cancer pain remains a significant clinical problem. To reduce side effects of treatment, intrathecal and epidural routes of administration have been used where appropriate to reduce the total dose of agent administered while achieving regional control. Resiniferatoxin (RTX), an ultrapotent capsaicin analog, gives long-term desensitization of nociception via C-fiber sensory neurons. We evaluate here the analgesic effect on rats of epidurally administered RTX, using latency of response to a thermal stimulus in unrestrained animals. Results were compared with those for systemically administered RTX. Vehicle or graded doses of RTX were injected subcutaneously (s.c.) or through an indwelling lumbar (L4) epidural catheter as a single dose. Both routes of application of RTX produced profound thermal analgesia, reaching a plateau within 4–6 h and showing no restoration of pain sensitivity over 7 days. Vehicle was without effect. For the epidural route, the effect was selective as expected for the targeted spinal cord region, whereas the subcutaneous administration of RTX had a generalized analgesic effect. At doses yielding a tripling of back paw withdrawal latency, epidural treatment was 25-fold more effective than the subcutaneous route of application. Consistent with the regional selectivity of the lumbar epidural route, the front paws showed no more effect than by systemic RTX treatment. Binding experiments with [ 3 H ]RTX provided further evidence of the segmental desensitization induced by epidural RTX. We conclude that epidural administration of RTX at the lumbar spinal level produces profound, long-lasting, segmental analgesia to C-fiber mediated pain in the rat.

Increased Excitability of Afferent Neurons Innervating Rat Urinary Bladder after Chronic Bladder Inflammation

The properties of bladder afferent neurons in L6 and S1 dorsal root ganglia of adult rats were evaluated after chronic bladder inflammation induced by 2 week treatment with cyclophosphamide (CYP; 75 mg/kg). Whole-cell patch-clamp recordings revealed that most (70%) of the dissociated bladder afferent neurons from control rats were capsaicin sensitive, with high-threshold long-duration action potentials that were not blocked by tetrodotoxin (TTX; 1 microM). These neurons exhibited membrane potential relaxations during voltage responses elicited by depolarizing current pulses and phasic firing during sustained membrane depolarization. After CYP treatment, a similar proportion (71%) of bladder afferent neurons were capsaicin sensitive with TTX-resistant spikes. However, the neurons were significantly larger in size (diameter 29.6 +/- 1.0 micrometer vs 23.6 +/- 0.8 micrometer in controls). TTX-resistant bladder afferent neurons from CYP-treated rats exhibited lower thresholds for spike activation (-25.4 +/- 0.5 mV) than those from control rats (-21.4 +/- 0.9 mV) and did not exhibit membrane potential relaxation during depolarization. Seventy percent of TTX-resistant bladder afferent neurons from CYP-treated rats exhibited tonic firing (average 12.3 +/- 1.4 spikes during a 500 msec depolarizing pulse) versus phasic firing (1.2 +/- 0.2 spikes) in normal bladder afferent neurons. Application of 4-aminopyridine (1 mM) to normal TTX-resistant bladder afferent neurons mimicked the changes in firing properties after CYP treatment. The peak density of an A-type K+ current (IA) during depolarizations to 0 mV in TTX-resistant bladder afferent neurons from CYP-treated rats was significantly smaller (42.9 pA/pF) than that from control rats (109.4 pA/pF), and the inactivation curve of the IA current was displaced to more hyperpolarized levels by approximately 15 mV after CYP treatment. These data suggest that chronic inflammation induces somal hypertrophy and increases the excitability of C-fiber bladder afferent neurons by suppressing IA channels. Similar electrical changes in sensory pathways may contribute to cystitis-induced pain and hyperactivity of the bladder.

Neuropeptide regulation of proinflammatory cytokine responses.

Severe traumatic injuries and infections are frequently accompanied by life-threatening shock and are associated with increases in the proinflammatory cytokines, particularly tumor necrosis factor alpha (TNF-alpha). The body's first perception of injury is the nociceptive or pain response. This response is induced at the site of injury and is transmitted systemically by sensory neuropeptides, the tachykinins, released from sensory afferent c-fiber neurons. We studied the role of tachykinins in regulating the production of proinflammatory cytokines induced by the administration of bacterial lipopolysaccharide. Destruction of terminal sensory nerve endings before lipopolysaccharide administration abrogates tachykinin synthesis and down-regulates TNF-alpha transcription and secretion. In contrast, the responses of interleukins-1 and -6 are unaffected. Pretreating animals with an antagonist for the substance P-specific NK-1 receptor also down-regulated the TNF-alpha response, whereas blockade of the NK-2 receptor had no effect. These findings indicate that substance P contributes to the induction of those cytokines that are involved in precipitating the shock response.

Neurogenic inflammation: with additional discussion of central and perceptual integration of nonneurogenic inflammation.

The Working Group on Neurogenic Inflammation proposed 11 testable hypotheses in the three domains of neurogenic inflammation, perceptual and central integration, and nonneurogenic inflammation. The working group selected the term people reporting chemical sensitivity (PRCS) to identify the primary subject group. In the domain of neurogenic inflammation, testable hypotheses included: PRCS have an increased density of c-fiber neurons in symptomatic tissues; PRCS produce greater quantities of neuropeptides and prostanoids than nonsensitive subjects in response to exposure to low-level capsaicin or irritant chemicals; PRCS have an increased and prolonged response to exogenously administered c-fiber activators such as capsaicin; PRCS demonstrate augmentation of central autonomic reflexes following exposure to agents that produce c-fiber stimulation; PRCS have decreased quantities of neutral endopeptidase in their mucosa; exogenous neuropeptide challenge reproduces symptoms of PRCS. In the domain of perceptual and central integration, testable hypotheses included: PRCS have alterations in adaptation, habituation, cortical representation, perception, cognition, and hedonics compared to controls; the qualitative and quantitative interactions between trigeminal and olfactory systems are altered in PRCS; higher integration of sensory inputs is altered in PRCS. In the domain of nonneurogenic inflammation, testable hypotheses included: increased inflammation is present in PRCS in symptomatic tissues and is associated with a heightened neurosensory response; PRCS show an augmented inflammatory response to chemical exposure. The working group recommended that studies be initiated in these areas.

Guinea pig visceral C-fiber neurons are diverse with respect to the K+ currents involved in action-potential repolarization.

1. Intracellular recordings were made from C-fiber neurons identified by antidromic conduction velocity in intact guinea pig nodose ganglia maintained in vitro, and whole-cell patch clamp recordings were made from dissociated guinea pig nodose neurons to investigate the contribution of various K+ conductances to action-potential repolarization. 2. The repolarizing phase of the intracellularly recorded action potential was prolonged in a concentration-dependent manner by charybdotoxin (Chtx; EC50 = 39 nM) or iberiatoxin (Ibtx; EC50 = 48 nM) in a subpopulation of 16/36 C-fiber neurons. In a subset of these experiments, removal of extracellular Ca2+ reversibly prolonged action-potential duration (APD) in the same 4/9 intracellularly recorded C-fiber neurons affected by Chtx (> or = 100 nM). These convergent results support that a Ca(2+)-activated K+ current (IC) contributes to action-potential repolarization in a restricted subpopulation of C-fiber neurons. 3. Tetraethylammonium (TEA; 1-10 mM) increased APD considerably further in the presence of 100-250 nM Chtx or Ibtx, or in nominally Ca(2+)-free superfusate in 14/14 intracellularly recorded C-fiber neurons. TEA affected APD similarly in subpopulations of neurons with and without IC, suggesting that a voltage-dependent K+ current (IK) contributes significantly to action-potential repolarization in most nodose C-fiber neurons. 4. Substitution of Mn2+ for Ca2+ reduced outward whole-cell currents elicited by voltage command steps positive to -30 mV (2-25 ms) in a subpopulation of 21/36 dissociated nodose neurons, supporting the heterogeneous expression of IC. The kinetics of outward tail current relaxations (tau s of 1.5-2 ms) measured at the return of 2-3 ms depolarizing steps to -40 mV were indistinguishable in neurons with and without IC, precluding a separation of the nodose IC and IK by a difference in deactivation rates. 5. Chtx (10-250 nM) reduced in a subpopulation of 3/8 C-fiber neurons the total outward current elicited by voltage steps depolarized to -30 mV in single microelectrode voltage-clamp recordings. TEA (5-10 mM) further reduced outward current in the presence of 100-250 nM Chtx in all eight experiments. The Chtx-sensitive current was taken to represent IC, and the TEA-sensitive current, the IK component contributing to action-potential repolarization. 6. Rapidly inactivating current (IA) was implicated in action-potential repolarization in a subpopulation of intracellularly recorded C-fiber neurons. In 4/7 neurons, incremented hyperpolarizing prepulses negative to -50 mV progressively shortened APD.(ABSTRACT TRUNCATED AT 400 WORDS)

Role of eicosanoids in hyperpnea-induced airway responses in guinea pigs

Guinea pigs mechanically hyperventilated with dry gas exhibit hyperpnea-induced bronchoconstriction (HIB) and hyperpnea-induced bronchovascular hyperpermeability (HIBVH). Tachykinins released from airway C-fiber neurons are the central mediators of guinea pig HIB but play only a contributory role in HIBVH. Recent studies suggest that eicosanoid mediators can provoke bronchoconstriction and bronchovascular hyperpermeability, are released by dry gas hyperpnea, and can themselves elicit or modulate tachykinin release. We therefore hypothesized that eicosanoids may participate in HIB and/or HIBVH. To test these hypotheses, we analyzed respiratory system resistance changes and Evans blue-labeled albumin extravasation into the airways of 60 tracheostomized and mechanically ventilated guinea pigs. Animals were subjected to 10 min of isocapnic dry gas hyperpnea or to quiet breathing of humidified gas and received as pretreatment either piroxicam, a cyclooxygenase (CO) inhibitor; A-63162, a 5-lipoxygenase (5-LO) inhibitor; BW-755c, a combined CO and 5-LO inhibitor; ICI-198,615, a leukotriene D4 receptor antagonist; or no drug. HIB was substantially (50-80%) reduced by each of the four eicosanoid-modulating drugs. In contrast, HIBVH was reduced only by BW-755c, and this effect occurred only within the extrapulmonary airways (42% reduction). These data indicate that both CO and 5-LO products, including leukotriene D4, participate in the pathogenesis of HIB but that, like tachykinins, they play only a small contributory role in HIBVH. Together with our previous demonstration that sensory neuropeptide release is critical for the occurrence of HIB, we conclude that the roles of eicosanoids and tachykinins in guinea pig HIB are interdependent.

Electrophysiological properties and chemosensitivity of acutely isolated nodose ganglion neurons of the rabbit

Neurons in the nodose ganglion were enzymatically dissociated from adult rabbits and electrophysiologically examined within 2 h. About 90% of the neurons survived the dissociation procedure. Their resting membrane potential (−59 ± 0.6 mV), time constant (5.7 ± 0.5 ms), input resistance ( 80 ± 5.3 MΩ ), action potential properties (amplitude, 79 ± 1.2 mV; overshoot 21 ± 1 0 mV; duration 5.2 ± 0.1 ms; threshold, −38 ± 0.9 mV; and fast spike afterhyperpolarizaton, 10 ± 0.5 mV, 64 ± 3.8 ms) were not different from values obtained from nodose neurons in intact ganglion in vitro and in vivo. An unusually long duration spike afterhyperpolarization observed in about 35% of nodose neurons in intact ganglion was demonstrated in about 28% of the acutely isolated neurons. The percentage of isolated neurons responding to bath applied acetylcholine, bradykinin, serotonin and histamine was similar to those reported for neurons in the intact ganglia. We conclude that the electrophysiological and chemoreceptive properties of acutely isolated adult rabbit nodose neurons are similar to those observed for neurons in intact ganglia. Thus the availability of large numbers of acutely isolated adult nodose neurons should allow multidisciplinary studies of vagal afferent C-fiber neurons not readily obtainable in the intact ganglion.

Endogenous sensory neuropeptide release enhances nonspecific airway responsiveness in guinea pigs.

To test whether endogenous sensory neuropeptide release results in airway hyperresponsiveness to exogenous bronchoconstrictor stimuli, male Camm-Hartley guinea pigs were exposed either to capsaicin aerosol for 10 min (CAP-AER) or to saline aerosol (SAL-AER) as a control condition. The following day, animals were anesthetized, tracheostomized, and beta-adrenergically blocked with propranolol, and their bronchoconstrictor responses to intravenously administered acetylcholine (ACh), neurokinin A (NKA), or capsaicin were measured. The bronchoconstriction induced by isocapnic dry gas hyperpnea also was assessed. Compared with the SAL-AER control group, the CAP-AER-treated animals exhibited augmented bronchoconstrictor responses to ACh and NKA. In contrast, the SAL-AER and CAP-AER groups had equivalent bronchoconstrictor responses to dry gas hyperpnea and to intravenously administered capsaicin. CAP-AER treatment caused neutrophilic airway inflammation, as reflected in increased numbers of neutrophils in bronchoalveolar lavage fluid obtained from CAP-AER-treated animals. Ablation of airway c-fiber neuron function (by chronic pretreatment with capsaicin prior to capsaicin aerosol inhalation) eliminated the ACh hyperresponsiveness observed in the CAP-AER-treated animals, demonstrating that sensory nerve products play a key role in the development of this nonspecific hyperresponsiveness. Our results demonstrate that sensory nerve stimulation with capsaicin aerosol leads to nonspecific bronchoconstrictor hyperresponsiveness and cellular airway inflammation, and thus disclose another potentially important role of sensory nerves in regulating airway function.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of gastric acid suppression in the treatment of gastro-oesophageal reflux disease.

Gastro-oesophageal reflux disease is a common condition with a complex pathophysiology. Despite the spectrum of abnormalities, gastric acid has a central role in mucosal damage, and the mainstay of medical treatment is suppression of gastric acid secretion. The results of antisecretory treatment as assessed by endoscopic healing are reviewed. H2 receptor antagonists give more rapid symptom relief than placebo and can produce endoscopic improvement in 31-88% of cases depending on the severity of oesophagitis. Complete healing, however, is seen only in 27-45% of patients and these have mainly grades I-II disease. Improved healing rates can be obtained by increasing the degree of acid suppression or the length of treatment. The addition of a prokinetic agent may be beneficial. Omeprazole heals 67-92% of patients overall and although most successful in the lower grades of oesophagitis, can also heal 48-62% of patients with grade IV disease. The degree and rate of healing seem to be related to the reduction in oesophageal acid exposure and thus may correlate with the degree and duration of acid suppression over 24 hours obtained by the various treatments. The underlying pathophysiology is unchanged, however, and long term treatment may be needed to maintain remission.

IgE-challenged human lung mast cells excite vagal sensory neurons in vitro.

Substances released from immunoglobin (Ig) E-stimulated mast cells are likely to be among the chemical mediators responsible for changes in the vagal component of airway reactivity. We have attempted to identify a direct role for mast cell mediators in the control of visceral afferent excitability by examining intracellular electrophysiological changes in vagal neurons after application of extracts prepared from purified and IgE-stimulated human lung mast cells (HLMC). HLMC's, applied by superfusion or by focal pressure ejection from micropipettes, reversibly enhanced the excitability of a subpopulation of rabbit visceral sensory C-fiber neurons by 1) abolishing the slow Ca2+-dependent post-spike after hyperpolarization that uniquely resides in these neurons and controls their spike frequency, 2) depolarizing the cell membrane potential, and 3) increasing membrane input resistance. Control HLMC prepared by subjecting purified human lung mast cells to normal goat serum had no measurable affects on neuronal excitability. The immunologically released constituents responsible for these excitability changes are likely to be lipid mediators, because essentially all biological activity is extractable into an organic phase after methanol-chloroform solvent extraction of the HLMC preparations. These results provide the first unambiguous evidence that products released from immunologically challenged HLMC's directly affect visceral afferent nerve cell function.

Central vagal organization in rats: An electrophysiological study

The organization of the vagal nuclei was studied electrophysiologically in chloralose-anesthetized rats by analyzing the field potentials and unitary responses evoked in the nuclei by stimulation of the cervical vagus nerve. The rostral part of the nucleus commissuralis yielded only a long-latency response to stimulation of this nerve, suggesting that this region receives projections solely of nonmyelinated afferent fibers. In the nucleus tractus solitarius the stimulation elicited both short-latency and long-latency responses, indicating converging projections of myelinated and nonmyelinated afferents. A long-latency response was recorded diffusely within n. commissuralis and n. tractus solitarius of the contralateral side, whereas a short-latency response was restricted to a midline area, the caudal n. commissuralis, and the most medial part of n. tractus solitarius adjacent to it. These observations also suggest a difference in projections of myelinated and nonmyelinated afferents. Two types of motor neurons were identified in the dorsal vagal nucleus by antidromic activation: one with B-fiber axons and the other with C-fiber axons. C-Fiber motor neurons were characterized by the large positivity of the spike and the presence of an inflection in the rising phase of the spike, presumably between the initial segment and somatodendritic components. The latter component was readily blocked by repetitive stimulation. In the nucleus ambiguus, stimulation of the vagus nerve produced the earliest antidromic response of A-fiber motor neurons accompanied by multiple orthodromic responses of short and long latencies. Electrolytic lesions of the dorsomedial medulla oblongata abolished all potentials in n. ambiguus except the antidromic one, indicating that all the orthodromic responses were generated via the vagal sensory nuclei sinuated dorsomedially.