Sensory Afferent Nerves Research Articles

Optical measurement of swelling and water transport in spinal cord slices from aquaporin null mice

Water movement between cells and interstitium in spinal cord and brain occurs during neural signal transduction and in response to injuries such as ischemia and blunt trauma. At least two aquaporin-type water channels are expressed in spinal cord: AQP1 in afferent sensory nerve fibers in the superficial layers of the dorsal horn, and AQP4 in glial cells throughout gray matter. An imaging method was developed to map thickness changes in viable spinal cord and brain slices cut by a vibratome, and applied to measure osmotically induced water transport in spinal cord slices from wildtype and aquaporin knockout mice. Spinal cord slices (300 μm thickness) were mounted in a perfusion chamber with <2 s exchange time, and transmitted light (565 nm) was imaged by a CCD camera. Changes in slice thickness were mapped from the amount of light passing through a thin (∼100 μm) layer of perfusate bathing the slice, in which hemoglobin (6 mg/ml) was added to the perfusate as an inert absorbing chromophore. In response to osmotic challenges imposed by changing perfusate osmolality by 100 mOsm, transmitted light intensity changed reversibly with approximately mono-exponential kinetics whose initial rate depended upon position in the slice. In the superficial dorsal horn where AQP1 is strongly expressed, the rate of osmotic swelling was 7.0±1.3 μm/s in wildtype mice and 2.0±0.2 μm/s in AQP1 null mice; osmotic swelling was slower in deeper lamina of dorsal horn, and was decreased in AQP4 but not AQP1 null mice. These results establish a simple imaging method to map changes in water content of spinal cord slices, and provide evidence that aquaporins facilitate osmotic water transport in functionally relevant areas of the spinal cord.

Herpes zoster in older adults. (Duke University Medical Center, Durham, NC) Clinical Infectious Diseases. 2001;32:1481–1486.

Herpes zoster (HZ) strikes millions of older adults annually worldwide and disables a substantial number of them via postherpetic neuralgia (PHN). Key aged‐related clinical, epidemiological, and treatment features of zoster and PHN are reviewed in this article. HZ is caused by renewed replication and spread of the varicella‐zoster virus (VZV) in sensory ganglia and afferent peripheral nerves in the setting of age‐related, disease‐related, and drug‐related decline in cellular immunity to VZV. VZV‐induced neuronal destruction and inflammation causes the principal problems of pain, interference with activities in daily living, and reduced quality of life in elderly patients. Recently, attempts to reduce or eliminate HZ pain have been bolstered by the findings of clinical trials that antiviral agents and corticosteroids are effective treatment for HZ and that tricyclic antidepressants, topical lidocaine, gabapentin, and opiates are effective treatment for PHN. Although these advances have helped, PHN remains a difficult condition to prevent and treat in many elderly patients.Comment by Miles Day, M.D. This article reviews the epidemiology clinical features diagnosis and treatment of acute herpes zoster. It also describes the treatment of postherpetic neuralgia. While this is a good review for the primary care physician, the discussion for the treatment for both acute herpes zoster and postherpetic neuralgia do not mention invasive therapy. It is well documented in pain literature that sympathetic blocks with local anesthetic and steroid as well as subcutaneous infiltration of active zoster lesions not only facilitate the healing of acute herpes zoster but also prevents or helps decrease the incidence of postherpetic neuralgia. All patients who present to the primary care physician with acute herpes zoster should have an immediate referral to a pain management physician for invasive therapy.The treatment of postherpetic neuralgia is a challenging experience both for the patient and the physician. While the treatments that have been discussed in this article are important, other treatments are also available. Regional nerve blocks including intercostal nerve blocks, root sleeve injections, and sympathetic blocks have been used in the past to treat postherpetic neuralgia. If these blocks are helpful, one can proceed with doing crynourlysis of the affected nerves or also radio‐frequency lesioning. Spinal cord stimulation has also been used for those patients who are refractory to noninvasive and invasive therapy. While intrathecal methylprednisolone was shown to be effective in the study quoted in this article one must be cautious not to do multiple intrathecal steroid injections in these patients. Multilple intrathecal steroid injections can lead to archnoiditis secondary to the accumulation of the steroid on the nerve roots and in turn causing worsening pain.

Cis-Urocanic Acid Stimulates Neuropeptide Release from Peripheral Sensory Nerves

Previous studies using an antibody to cis-urocanic acid and mast-cell-depleted mice implicated both cis-urocanic acid and mast cells in the mechanisms by which ultraviolet B light suppresses systemic contact hypersensitivity responses in mice. In the absence of a direct stimulatory effect of cis-urocanic acid on connective tissue mast cells, an indirect association was investigated. A blister induced in the rat hind footpad was used to examine the effects of slowly perfused cis-urocanic acid on cutaneous blood flow. cis-Urocanic acid but not trans-urocanic acid increased microvascular flow by a mechanism largely dependent on the combined activity of the neuropeptides, substance P and calcitonin gene-related peptide. Perfusion of cis-urocanic acid over the base of blisters induced in sensory-neuropeptide-depleted rats did not have any stimulatory effect above that seen with perfusion of cis-urocanic acid together with neuropeptide receptor antagonists in control rats. There was a small direct effect of cis-urocanic acid on microvascular blood flow. As both substance P and calcitonin gene-related peptide could directly degranulate connective tissue mast cells, this study suggests that cis-urocanic acid indirectly activates mast cells via its effects on peripheral terminals of unmyelinated primary afferent sensory nerves. cis-Urocanic-acid-induced neuropeptides may also contribute to ultraviolet-B-induced cutaneous inflammation and alterations to Langerhans cell activity.

Four response stages of capsaicin-sensitive primary afferent neurons to capsaicin and its analog: gastric acid secretion, gastric mucosal damage and protection.

Capsaicin is the active component of red hot peppers, which modifies specifically the capsaicin-sensitive sensory afferent nerves. The action of capsaicin is an initial short-lasting stimulation, which is followed by desensitization to capsaicin itself, and to other stimuli of afferent sensory nerves. Four response stages of capsaicin-sensitive primary afferents exist to capsaicin, depending on the dose and duration of exposure to the drug. These are excitation, a sensory blocking effect, long-term selective neurotoxic impairment, and irreversible cell destruction. The possible roles of four stages of capsaicin-sensitive primary afferents can be evaluated in relation to gastric acid secretion, and to the details of the defensive side of gastric mucosa against different chemicals, physical agents, drugs and other pathological stress. Capsaicin inhibited the gastric acid secretion in pylorus-ligated rats when it was given intragastrically at a dose of 0.4-1.8 microg/kg. Small doses of capsaicin (up to 800 microg, i.g.) produced a dose-dependent inhibition (ID50 = 400 microg), and its inhibitory effect was exerted for 1 h in healthy human subjects. While a small dose (5 microg/kg) of capsaicin caused inhibition, a high dose (50-100 mg/kg) enhanced the gastric mucosal lesions productivity by causing hyperacidity in pylorus-ligated animals. Capsaicin and its analog inhibited the development of different chemically induced gastric mucosal damage in various experimental models if they were given intragastric doses (microg/kg). The final effects of capsaicin depend on the dosage and timing. The different effects are excitation, a sensory-blocking effect, long-term selective neurotoxic impairment and irreversible cell destruction.

Involvement of primary sensory afferents, postganglionic sympathetic nerves and mast cells in the formalin-evoked peripheral release of adenosine

Injection of formalin into the rat hind paw produces a dose-dependent local peripheral release of adenosine. Low doses of formalin (0.5–2.5%) evoke release during the first 10 min following injection, while a high dose of formalin (5%) evokes release lasting for 60 min. The current study was designed to determine the possible origin of release produced by two doses of formalin (1.5% and 5%). Microdialysis probes were implanted into the subcutaneous tissue under the glabrous skin of the hind paw of anaesthetized rats, and adenosine was determined by high performance liquid chromatography. Pretreatment with capsaicin, a neurotoxin selective for unmyelinated small diameter primary afferent nerves, markedly reduced the adenosine released by 1.5% formalin and the early phase of release by 5% formalin. Acute injection of 1% capsaicin to the hind paw of untreated rats also induced adenosine release. Pretreatment with 6-hydroxydopamine, a neurotoxin selective for sympathetic postganglionic nerve terminals, had no effect on release evoked by 1.5% formalin, but significantly reduced adenosine release during the late phase of release induced by 5% formalin. Pretreatment with compound 48/80, which degranulates mast cells, had no effect on adenosine release evoked by either concentration of formalin. We conclude that the origin of the adenosine released peripherally by formalin depends on the formalin concentration. At the lower concentration (1.5%), release is predominately from unmyelinated sensory afferent nerve terminals, while at the higher concentration (5%), unmyelinated afferent nerve terminals are involved in the early phase, while sympathetic postganglionic nerve terminals are involved in the later phase. Mast cells do not contribute to release of adenosine evoked by either concentration of formalin.

Inhibition of Neurogenic Inflammation by the Amazonian Herbal Medicine Sangre de Grado

This study was designed to determine if the Amazonian medicinal sangre de grado, confers benefit by suppressing the activation of sensory afferent nerves. (i) vasorelaxation of rat mesenteric arteries in response to calcitonin gene-related peptide; (ii) rat paw edema in response to protease- activating peptide receptor 2-activating peptide; (iii) rat paw hyperalgesia in response to low-dose protease-activating peptide receptor 2-activating peptide or prostaglandin E2; (iv) gastric hyperemia in response luminal capsaicin; (v) a clinical trial of a sangre de grado balm in pest control workers. The parent botanical was fractionated for evaluation of potential active components. In preconstricted rat mesenteric arteries, highly diluted sangre de grado (1:10,000) caused a shift to the right of the calcitonin gene-related peptide dose-response curve (p < 0.01). Paw edema in response to protease-activating peptide receptor 2-activating peptide (500 microg) was reduced by as single topical administration sangre de grado balm (1% concentration, p < 0.01) for at least 6 h. Hyperalgesia induced by either low-dose protease-activating peptide receptor 2-activating peptide (50 microg) or prostaglandin E2 was prevented by sangre de grado balm. A fraction possessing analgesic and capsaicin antagonistic properties was isolated and high-performance liquid chromatography and gas chromatography-mass spectrometry analysis indicated that it was a proanthocyandin oligomer. In pest control workers, sangre de grado balm (Zangrado) was preferred over placebo, for the relief of itching, pain, discomfort, edema, and redness in response to wasps, fire ants, mosquitoes, bees, cuts, abrasions, and plant reactions. Subjects reported relief within minutes. We conclude that sangre de grado is a potent inhibitor of sensory afferent nerve mechanisms and supports its ethnomedical use for disorders characterized by neurogenic inflammation.

The pathophysiology of migraine.

Migraine results from episodic changes in central nervous system physiologic function in hyperexcitable brain manifested by abnormal energy metabolism, lowered threshold for phosphene generation, and increased contingent negative variation. Human functional magnetic resonance imaging and magnetoencepholography data strongly suggest that aura is caused by cortical spreading depression. Brain hyperexcitability may be caused by low magnesium levels, mitochondrial abnormalities with abnormal phosphorylation of adenosine 5'-diphosphate, a dysfunction related to nitric oxide, or calcium channelopathy. Low magnesium can result in opening of calcium channels, increased intracellular calcium, glutamate release, and increased extracellular potassium, which may in turn trigger cortical spreading depression. Mitochondrial dysfunction has been suggested by a low phosphocreatine:Pi ratio and a possible response by migraine patients to riboflavin prophylaxis. Nitroglycerine administration results in a delayed migraine-like headache in migraine patients but not in control patients, and a nonspecific nitric oxide synthase inhibitor aborted migraine at 2 hours in the majority of tested migraine patients compared to controls. Many patients with familial hemiplegic migraine have a missense mutation in the P/Q calcium channel, so that this form of migraine, at least, is associated with a demonstrable calcium channelopathy. The generation of migraine occurs centrally in the brain stem, sometimes preceded by cortical spreading depression and aura. Activation of the trigeminovascular system stimulates perivascular trigeminal sensory afferent nerves with release of vasoactive neuropeptides, resulting in vasodilation and transduction of central nociceptive information. There is then a relay of pain impulses to central second- and third-order neurons and activation of brain stem autonomic nuclei to induce associated symptoms.

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Circulating sensory peptide levels within 24 h of human bone fracture

We designed this study to examine the circulatory levels of wound modulatory peptides [substance P (SP), calcitonin gene related peptide (CGRP] in patients with muscle injuries with bone fractures and within 24 h of the injury. The peripheral plasma levels of these sensory nerve peptides were measured on hospital admission (OA) and 24 h post-injury (PI), using ELISA technique. Mean (s.d) ng/liter of CGRP was higher in patients OA (270 ± 199), and PI (205 ± 176); than the controls (3 ± 81) P < 0.05. Substance P also increased in the patients OA: 101 ± 50; PI: 46 ± 3 than controls [8 ± 9] P < 0.001. Elastase (predictor of posttraumatic complication) was examined and there was no significant differences between patients and control samples ( P = NS). This study shows that sensory nerve peptides are increased in bone fracture related injuries up to 24 h after injury. An intact nociceptor system of primary afferent sensory nerves is important for the initiation of the inflammatory process and successful tissue repair as dysfunction of this system could be a contributing factor for a delayed wound healing.

Herpes zoster in older adults.

Herpes zoster (HZ) strikes millions of older adults annually worldwide and disables a substantial number of them via postherpetic neuralgia (PHN). Key age-related clinical, epidemiological, and treatment features of zoster and PHN are reviewed. HZ is caused by renewed replication and spread of varicella-zoster virus (VZV) in sensory ganglia and afferent peripheral nerves in the setting of age-related, disease-related, and drug-related decline in cellular immunity to VZV. VZV-induced neuronal destruction and inflammation causes the principal problems of pain, interference with activities of daily living, and reduced quality of life in elderly patients. Recently, attempts to reduce or eliminate HZ pain have been bolstered by the findings of clinical trials that antiviral agents and corticosteroids are effective treatment for HZ and that tricyclic antidepressants, topical lidocaine, gabapentin, and opiates are effective treatment for PHN. Although these advances have helped, PHN remains a difficult condition to prevent and treat in many elderly patients.

Levels of vasodilators (SP, CGRP) and vasoconstrictor (NPY) peptides in early human burns

An intact nociceptor system of primary afferent sensory nerves is important for the initiation of the inflammatory process and successful tissue repair. Dysfunction of this system could be a contributing factor for delayed wound healing in humans. We examined the levels of vasodilators [substance P (SP), calcitonin gene-related peptide (CGRP)] and a vasoconstrictor peptide [neuropeptide Y (NPY)] in the peripheral blood samples of patients with burns covering from 20 to 75% of body surface area. Thirteen patient samples were obtained immediately on admission (OA), which was within 12 h of the thermal injury, and 24 h post-admission (PA). Enzyme immunoassay techniques were used for the measurement of the neuropeptides. In addition, an inflammatory marker, tumour necrosis factor-alpha (TNF-alpha), and a myofibrillar protein, creatine kinase (CK), were examined and compared with levels in 13 control subjects. CGRP was high OA and the levels were maintained PA (P < 0.05). SP was also significantly high at both sampling times (P < 0.05). Although TNF-alpha and NPY were somewhat higher in the patients' samples than in the control samples, these levels were not statistically significant (P = NS). CK was higher OA (P < 0.01) than PA (P < 0.04), compared to controls. Plasma levels of SP and CGRP increased significantly in patients with thermal injuries. These peptides may yet be another group of neuromodulators playing a significant role in immune, pain, inflammatory and wound healing in burns.

Fever induction pathways: evidence from responses to systemic or local cytokine formation.

The immune and central nervous systems are functionally connected and interacting. The concept that the immune signaling to the brain which induces fever during infection and inflammation is mediated by circulating cytokines has been traditionally accepted. Administration of bacterial lipopolysaccharide (LPS) induces the appearance of a so-termed "cytokine cascade" in the circulation more or less concomitantly to the developing febrile response. Also, LPS-like fever can be induced by systemic administration of key cytokines (IL-1 beta, TNF-alpha, and others). However, anti-cytokine strategies against IL-1 beta or TNF-alpha along with systemic injections of LPS frequently lead to attenuation of the later stages of the febrile response but not of the initial phase of fever, indicating that cytokines are rather involved in the maintenance than in the early induction of fever. Within the last years experimental evidence has accumulated indicating the existence of neural transport pathways of immune signals to the brain. Because subdiaphragmatic vagotomy prevents or attenuates fever in response to intraperitoneal or intravenous injections of LPS, a role for vagal afferent nerve fibers in fever induction has been proposed. Also other sensory nerves may participate in the manifestation of febrile responses under certain experimental conditions. Thus, injection of a small dose of LPS into an artificial subcutaneous chamber results in fever and formation of cytokines within the inflamed tissue around the site of injection. This febrile response can be blocked in part by injection of a local anesthetic into the subcutaneous chamber, indicating a participation of cutaneous afferent nerve signals in the manifestation of fever in this model. In conclusion, humoral signals and an inflammatory stimulation of afferent sensory nerves can participate in the generation and maintenance of a febrile response.

DENSITY OF SYMPATHETIC AXONS IN SURAL NERVE BIOPSIES OF NEUROPATHY PATIENTS IS RELATED TO PAINFULNESS

In this study, differences of unmyelinated nerve fiber density in sural nerve biopsy material from patients suffering from neuropathies of unknown origin with (n = 14) or without pain (n = 13) were analyzed. Immunocytochemistry was applied to differentiate afferent sensory and efferent sympathetic nerve fibers. All patients were evaluated for deficits of small fiber function with thermotesting, quantitative sudomotor‐axon reflex‐testing and testing of painfulness of mechanical stimuli before performing the biopsy. No difference was found between patients with and without pain concerning clinical deficits or results in any of the neurophysiological examinations. There were also no histopathological differences concerning the density of afferent C‐fibers. However, absolute and relative density of efferent sympathetic nerve fibers was significantly higher in patients with painful neuropathy (P &lt; 0.001), although none of the patients demonstrated clinical sympathetic abnormalities. We conclude that an imbalance between afferent and sympathetic nerve fiber density in the periphery may contribute to neuropathic pain even in those patients without obvious clinical autonomic disturbances.

Neural integration and allergic disease

Changes in neural activity play a key role in many symptoms of allergic disease, including sneezing, coughing, itching, and ocular irritation, among others. The mechanisms underlying allergen-induced changes in neural activity (reflexes) are largely unknown and under active investigation. Allergic inflammation can affect neural activity on a variety of levels, including at the primary afferent sensory nerve, integrative centers of the central nervous system, autonomic ganglia, and autonomic neuroeffector junction. At the level of the afferent sensory nerve, mediators released after allergen exposure either directly or indirectly increase neuronal firing. At the level of sensory ganglia, which contain cell bodies that innervate a variety of organs, changes in neuronal excitability may lead to a generalization of allergic symptoms. In the central nervous system, where afferent inputs from throughout the body converge, allergic inflammation may be associated with central sensitization, leading to the modulation of the neural reflexes. Finally, at the autonomic ganglia and neuroeffector junction, allergic inflammation appears to be associated with enhanced ganglionic transmission and neurotransmitter release, respectively. Mechanisms by which allergen challenge affects neuronal activity at various levels of the nervous system are reviewed, with a primary emphasis on studies of airway physiologic factors. (J Allergy Clin Immunol 2000;106:S213-20.)

ROLE OF MITOGEN-ACTIVATED PROTEIN KINASE IN CHOLINERGIC STIMULATION OF CONJUNCTIVAL GOBLET CELL SECRETION.

Conjunctival goblet cells are a primary source for the mucous layer of the tear film. We showed previously that conjunctival goblet cell mucin secretion is under neural control as activation of afferent sensory nerves in the cornea stimulates mucin secretion.1 This neural reflex is mediated either by the parasympathetic and sympathetic nerves that surround the goblet cells, or by antidromic stimulation of the sensory nerves in the conjunctiva and collateral sensory nerves from the cornea. Exogenous addition of the parasympathetic agonist carbachol or the parasympathetic neuropeptide VIP stimulated conjunctival goblet cell secretion.2,3 Cholinergic agonists released from parasympathetic nerves bind to and activate G protein linked- M2 and M3 muscarinic receptors. In most tissues, activation of these receptors stimulates phospholipase C to hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-triphosphate (IP3) and diacylglycerol (DAG). IP3 binds to specific receptors on the endoplasmic reticulum to increase intracellular Ca2+. The increased intracellular Ca2+ either directly, or in combination with Ca2+/calmodulin-dependent protein kinases, activates mucin secretion. DAG in turn stimulates protein kinase C (PKC). In many tissues, cholinergic agonists also activate the mitogen-activated protein kinase (MAPK) signaling pathway used by growth factor receptors, which usually regulate cell growth and proliferation. Activation of the MAPK pathway by cholinergic agonists can occur through several mechanisms. One such mechanism is through transactivation of the EGF receptor in an EGF-independent manner.4 The activated recepter then serves as a scaffold for recruitment of Grb2-SoS complex via tyrosine phosphorylation of Shc.

Nonrenewal Statistics of Electrosensory Afferent Spike Trains: Implications for the Detection of Weak Sensory Signals

The ability of an animal to detect weak sensory signals is limited, in part, by statistical fluctuations in the spike activity of sensory afferent nerve fibers. In weakly electric fish, probability coding (P-type) electrosensory afferents encode amplitude modulations of the fish's self-generated electric field and provide information necessary for electrolocation. This study characterizes the statistical properties of baseline spike activity in P-type afferents of the brown ghost knifefish, Apteronotus leptorhynchus. Short-term variability, as measured by the interspike interval (ISI) distribution, is moderately high with a mean ISI coefficient of variation of 44%. Analysis of spike train variability on longer time scales, however, reveals a remarkable degree of regularity. The regularizing effect is maximal for time scales on the order of a few hundred milliseconds, which matches functionally relevant time scales for natural behaviors such as prey detection. Using high-order interval analysis, count analysis, and Markov-order analysis we demonstrate that the observed regularization is associated with memory effects in the ISI sequence which arise from an underlying nonrenewal process. In most cases, a Markov process of at least fourth-order was required to adequately describe the dependencies. Using an ideal observer paradigm, we illustrate how regularization of the spike train can significantly improve detection performance for weak signals. This study emphasizes the importance of characterizing spike train variability on multiple time scales, particularly when considering limits on the detectability of weak sensory signals.

Involvement of kinins, mast cells and sensory neurons in the plasma exudation and paw oedema induced by staphylococcal enterotoxin B in the mouse

Intraplantar injection of staphylococcal enterotoxin B induces long-lasting oedema mediated by both cyclooxygenase and lipoxygenase products as well as by neuropeptides from sensory nerves. This study was undertaken to further clarify the role of peripheral primary afferent sensory nerves in staphylococcal enterotoxin B (25 μg/paw)-induced plasma extravasation and oedema formation. The tachykinin NK 1 receptor antagonist ( S)-1-[2-[3-(3,4-dichlorophenyl)-1 (3-isopropoxyphenylacetyl)piperidin-3-yl] ethyl]-4-phenyl-1 azoniabicyclo [2.2.2]octane cloride (SR140333; 120 nmol/kg, s.c.+120 nmol/kg, i.v.) significantly inhibited plasma exudation and paw oedema evoked by staphylococcal enterotoxin B. The tachykinin NK 2 receptor antagonist ( S)- N-methyl- N[4-(4-acetylamino-4-phenyl piperidino)-2-(3,4-dichlorophenyl)butyl]-benzamide (SR48968) had no effect on the staphylococcal enterotoxin B-induced responses. The bradykinin B 2 receptor antagonist d-Arg-[Hyp 3,Thi 5, d-Tic 7,Oic 8]bradykinin (Hoe 140; 400 nmol/kg, i.v.) significantly reduced staphylococcal enterotoxin B-induced responses. The magnitude of the inhibition observed with Hoe 140 alone was similar to that caused by concomitant treatment of animals with SR140333 and Hoe 140, suggesting that there is a final common pathway. Additionally, SR140333 given alone reduced bradykinin (3 nmol/paw)-induced paw oedema. The vanilloid receptor antagonist N-[2-(4-chlorophenyl) ethyl]-1,3,4,5-tetrahydro-7,8-dihydroxy-2 H-2-benzazepine-2-carbothioamide (capsazepine; 100 μmol/kg) significantly reduced staphylococcal enterotoxin B-induced responses. The 5-HT receptor antagonist methysergide (10 mg/kg, i.v.) and the histamine H 1 receptor antagonist mepyramine (10 mg/kg, i.v.) produced a significant reduction in paw oedema whereas plasma exudation was reduced only by methysergide. In diabetic mice, exudation and oedema evoked by staphylococcal enterotoxin B were markedly reduced. Acute administration of insulin (20 UI/kg, s.c., 30 min before) did not restore the increased permeability induced by staphylococcal enterotoxin B. We conclude that plasma exudation and paw oedema in response to staphylococcal enterotoxin B are a consequence of a complex neurogenic response involving direct activation of vanilloid receptors on sensory nerves, release of kinins and subsequent activation of bradykinin B 2 receptors at a prejunctional level, and direct or indirect degranulation of mast cells.

Significance of neuropeptides released from afferent sensory nerves and cyclooxygenase (COX)-derived prostaglandins in adaptive cytoprotection induced by mild irritants

Significance of neuropeptides released from afferent sensory nerves and cyclooxygenase (COX)-derived prostaglandins in adaptive cytoprotection induced by mild irritants

Density of sympathetic axons in sural nerve biopsies of neuropathy patients is related to painfulness

In this study, differences of unmyelinated nerve fiber density in sural nerve biopsy material from patients suffering from neuropathies of unknown origin with (n=14) or without pain (n=13) were analyzed. Immunocytochemistry was applied to differentiate afferent sensory and efferent sympathetic nerve fibers. All patients were evaluated for deficits of small fiber function with thermotesting, quantitative sudomotor-axon reflex-testing and testing of painfulness of mechanical stimuli before performing the biopsy. No difference was found between patients with and without pain concerning clinical deficits or results in any of the neurophysiological examinations. There were also no histopathological differences concerning the density of afferent C-fibers. However, absolute and relative density of efferent sympathetic nerve fibers was significantly higher in patients with painful neuropathy (P<0.001), although none of the patients demonstrated clinical sympathetic abnormalities. We conclude that an imbalance between afferent and sympathetic nerve fiber density in the periphery may contribute to neuropathic pain even in those patients without obvious clinical autonomic disturbances.

AUTORADIOGRAPHIC LOCALIZATION OF TACHYKININ AND CALCITONIN GENE-RELATED PEPTIDE RECEPTORS IN ADULT URINARY BLADDER

In bladder, sensory afferent nerve fibers contain the "sensory neuropeptides" substance P (SP), neurokinin A (NKA) and calcitonin gene-related peptide (CGRP), which interact with tachykinin NK-1 and NK-2 receptors and CGRP receptors, respectively. The purpose of this study was to examine the autoradiographic distribution of these three receptor types in the human bladder, to determine whether the anatomic location of the receptors was consistent with their known functional roles. Specimens of urinary bladder from 9 patients (58-74 years) were obtained at cystectomy. Frozen sections of dome were labeled with [125I]-Bolton-Hunter [Sar9,Met(O2)11]-SP (NK-1 receptors), [125I]-[Lys5,Tyr(I2)7,MeLeu9,Nle10]-NKA(4-10) (NK-2 receptors) and [125I]-rat CGRP-I. Binding sites were visualized using emulsion autoradiography. NK-1 receptors were found over the endothelium of arterial blood vessels within the detrusor muscle and lamina propria, and over small vessels in the subepithelium. NK-2 receptors were seen over the detrusor muscle and very sparsely over blood vessels, whereas CGRP receptors were expressed densely over the smooth muscle layer of arteries and arterioles, and weakly over collecting venules. NK-1 and CGRP receptors were not observed over the detrusor muscle. Although the afferent nerves contain all three peptides, not all cell types express receptors for each peptide. The general distribution of receptors is in good agreement with the location of nerves, and with the known actions of SP and CGRP as vasodilator agents, and of NKA (but not SP or CGRP) in contracting the detrusor muscle.