Nociceptive Nerve Fibers Research Articles

Activity of corneal nociceptive nerve fibers during allergic challenge of the ocular surface

Abstract Purpose The aim of this work was to study in vitro the spontaneous and stimulus‐evoked electrical activity of corneal nociceptive nerve fibers during acute allergic inflammation of the ocular surface induced in the guinea‐pig. Methods Animals received i.p. 10% ovalbumin (OVA). 14 days later, a 10µl drop of OVA was applied topically to each eye. Blinking and scratching movements directed to the eye were measured during 10 min, and ocular symptoms (edema and hyperemia) and tear rate were measured. Animals were killed afterwards and both eyes were immediately excised and mounted in a superfused (32°C) recording chamber. Electrical activity of corneal sensory receptors was recorded from nerve filaments dissected from the ciliary nerves. Mechanical (calibrated von Frey hairs), thermal (bath solution temperature down to 20°C or up to 52°C), and chemical stimulation (30s‐pulses of 98%CO2) were performed. Spontaneous (SA) and stimulus‐evoked activity were analyzed. Results After the allergic challenge, eye‐scratching behavior was present in 4 out of 15 animals and blinking movements increased from 1±0.05 to 26±5. Tearing also increased compared to control (33±3 vs. 5±1 mm). Compared to naive eyes, proportion of nociceptors with SA (17% vs. 5%) and spontaneous discharge rate (0.13±0.07 vs. 0.01±0.01 imp/s) were increased. Mechanical threshold of mechano‐nociceptive units decreased significantly (0.37±0.05 vs. 0.89±0.13 mN). Chemosensitivity of polymodal nociceptors was slightly increased (1.87±0.42 vs. 1.34±0.23 imp/s). Conclusion Changes in corneal sensory nerve activity observed acutely after allergic challenge of the eye surface may constitute the basis of itching and discomfort sensations, and hypersensitivity observed in allergic patients.

Determining heat and mechanical pain threshold in inflamed skin of human subjects

In a previous article in the Journal of Visualized Experiments we have demonstrated skin microdialysis techniques for the collection of tissue-specific nociceptive and inflammatory biochemicals in humans. In this article we will show pain-testing paradigms that are often used in tandem with microdialysis procedures. Combining pain tests with microdialysis provides the critical link between behavioral and biochemical data that allows identifying key biochemicals responsible for generating and propagating pain. Two models of evoking pain in inflamed skin of human study participants are shown. The first model evokes pain with aid of heat stimuli. Heat evoked pain as described here is predominantly mediated by small, non-myelinated peripheral nociceptive nerve fibers (C-fibers). The second model evokes pain via punctuated pressure stimuli. Punctuated pressure evoked pain is predominantly mediated by small, myelinated peripheral nociceptive nerve fibers (A-delta fibers). The two models are mechanistically distinct and independently examine nociceptive processing by the two major peripheral nerve fiber populations involved in pain signaling. Heat pain is evoked with aid of the TSA II, a commercially available thermo-sensory analyzer (Medoc Advanced Medical Systems, Durham, NC). Stimulus configuration and delivery is handled with aid of specific software. Thermodes vary in size and shape but in principle consist of a metal plate that can be heated or cooled at various rates and for different periods of time. Algorithms assessing heat-evoked pain are manifold. In the experiments shown here, study participants are asked to indicate at what point they start experiencing pain while the thermode in contact with skin is heated at a predetermined rate starting at a temperature that does not evoke pain. The thermode temperature at which a subject starts experiencing pain constitutes the heat pain threshold. Mechanical pain is evoked with punctuated probes. Such probes are commercially available from several manufacturers (von Frey hairs). However, the accuracy of von Frey hairs has been criticized and many investigators use custom made punctuated pressure probes. In the experiments shown here eight custom-made punctuated probes of different weights are applied in consecutive order, a procedure called up-down algorithm, to identify perceptional deflection points, i.e., a change from feeling no pain to feeling pain or vice versa. The average weight causing a perceptional deflection constitutes the mechanical pain threshold.

Determining heat and mechanical pain threshold in inflamed skin of human subjects

In a previous article in the Journal of Visualized Experiments we have demonstrated skin microdialysis techniques for the collection of tissue-specific nociceptive and inflammatory biochemicals in humans. In this article we will show pain-testing paradigms that are often used in tandem with microdialysis procedures. Combining pain tests with microdialysis provides the critical link between behavioral and biochemical data that allows identifying key biochemicals responsible for generating and propagating pain. Two models of evoking pain in inflamed skin of human study participants are shown. The first model evokes pain with aid of heat stimuli. Heat evoked pain as described here is predominantly mediated by small, non-myelinated peripheral nociceptive nerve fibers (C-fibers). The second model evokes pain via punctuated pressure stimuli. Punctuated pressure evoked pain is predominantly mediated by small, myelinated peripheral nociceptive nerve fibers (A-delta fibers). The two models are mechanistically distinct and independently examine nociceptive processing by the two major peripheral nerve fiber populations involved in pain signaling. Heat pain is evoked with aid of the TSA II, a commercially available thermo-sensory analyzer (Medoc Advanced Medical Systems, Durham, NC). Stimulus configuration and delivery is handled with aid of specific software. Thermodes vary in size and shape but in principle consist of a metal plate that can be heated or cooled at various rates and for different periods of time. Algorithms assessing heat-evoked pain are manifold. In the experiments shown here, study participants are asked to indicate at what point they start experiencing pain while the thermode in contact with skin is heated at a predetermined rate starting at a temperature that does not evoke pain. The thermode temperature at which a subject starts experiencing pain constitutes the heat pain threshold. Mechanical pain is evoked with punctuated probes. Such probes are commercially available from several manufacturers (von Frey hairs). However, the accuracy of von Frey hairs has been criticized and many investigators use custom made punctuated pressure probes. In the experiments shown here eight custom-made punctuated probes of different weights are applied in consecutive order, a procedure called up-down algorithm, to identify perceptional deflection points, i.e., a change from feeling no pain to feeling pain or vice versa. The average weight causing a perceptional deflection constitutes the mechanical pain threshold.

Nerve fibers that were not stained with the non-specific acetylcholinesterase (NsAchE) method, and TRPV1- and IB4-positive nerve fibers in the rat cornea

Previously, we noticed the presence of nerve fiber-like structures in a whole mount preparation of the rat cornea that had not been stained with the non-specific acetylcholinesterase (NsAchE) method. These nerve-like fibers were projected into the central area of the cornea, forming a mesh-like pattern. The aim of this study is to examine the properties of these mesh-like fibers using the following two methods: their sensitivity to capsaicin and the detection of isolectin B4 (IB4)- and capsaicin receptor TRPV1 (transient receptor potential vanilloid 1)-reactivities. The mean disappeared area of non-stained fibers after NsAchE treatment was 26% of the total areas in the neonatally capsaicin-treated cornea. Bunches composed of fine IB4-positive nerve fibers were seen in a whole mount preparation. There were connections between the bunches, producing a mesh-like pattern similar to that of the fibers that were not stained with NsAchE. Fine TRPV1-immunoreactive (ir) nerve fibers were also shown to form bunches, with connections between each bunch observed in whole mount preparations. Thus, TRPV1-ir nerve fibers seem to densely innervate the rat corneal subepithelial stroma and are distinct from the NsAchE-positive nerve fibers. The TRPV1-ir fine nerve fibers overlapped with the IB4-positive nerve fibers, suggesting that the mesh-like fibers that were not stained with NsAchE are fine nociceptive sensory nerve fibers because of their sensitivity to capsaicin and similar distribution pattern to IB4- and TRPV1-positive nerve fibers.

The Beneficial Effects of C-Peptide on Diabetic Polyneuropathy

Diabetic polyneuropathy (DPN) is a common complication in diabetes. At present, there is no adequate treatment, and DPN is often debilitating for patients. It is a heterogeneous disorder and differs in type 1 and type 2 diabetes. An important underlying factor in type 1 DPN is insulin deficiency. Proinsulin C-peptide is a critical element in the cascade of events. In this review, we describe the physiological role of C-peptide and how it provides an insulin-like signaling function. Such effects translate into beneficial outcomes in early metabolic perturbations of neural Na+/K+-ATPase and nitric oxide (NO) with subsequent preventive effects on early nerve dysfunction. Further corrective consequences resulting from this signaling cascade have beneficial effects on gene regulation of early gene responses, neurotrophic factors, their receptors, and the insulin receptor itself. This may lead to preventive and corrective results to nerve fiber degeneration and loss, as well as, promotion of nerve fiber regeneration with respect to sensory somatic fibers and small nociceptive nerve fibers. A characteristic abnormality of type 1 DPN is nodal and paranodal degeneration with severe consequences for myelinated fiber function. This review deals in detail with the underlying insulin-deficiency-related molecular changes and their correction by C-peptide. Based on these observations, it is evident that continuous maintenance of insulin-like actions by C-peptide is needed in peripheral nerve to minimize the sequences of metabolic and molecular abnormalities, thereby ameliorating neuropathic complications. There is now ample evidence demonstrating that C-peptide replacement in type 1 diabetes promotes insulin action and signaling activities in a more enhanced, prolonged, and continuous fashion than does insulin alone. It is therefore necessary to replace C-peptide to physiological levels in diabetic patients. This will have substantial beneficial effects on type 1 DPN.

Orthodontic treatment and management of limited mouth opening and oral lesions in a patient with congenital insensitivity to pain: case report

Congenital insensitivity to pain is a rare clinical syndrome characterized by dramatic impairment of pain perception since birth and is generally caused by a hereditary sensory and autonomic neuropathy with loss of the small-calibre, nociceptive nerve fibres. We report a 9-year-old case, with a generalized congenital insensitivity to pain. The patient was referred to our Department by a private orthodontist for severe limited mouth opening and multiple oral ulcers which greatly worsened after starting the orthodontic treatment. The management of his oral lesions of the limited mouth opening and of the orthodontic treatment are described. The management approach aimed to improve mandibular range of motion and associated stretching and a self-modeling mouthguard to avoid cheek self-biting. This protocol allowed continuing the orthodontic treatment to restore the occlusion. Finally, good occlusion, normal function and better quality of patient's life were achieved.

Somatosensory Hypersensitivity in the Referred Pain Area in Patients With Chronic Biliary Pain and a Sphincter of Oddi Dysfunction: New Aspects of an Almost Forgotten Pathogenetic Mechanism

Somatosensory hyperalgesia in the referred pain area (RPA) in patients with acute or chronic abdominal pain syndromes may result from the convergence of nerve fibers from visceral and somatic tissues at the spinal and supraspinal levels. Chronic biliary pain in patients with the postcholecystectomy syndrome (i.e., biliary hypersensitivity) may be explained by persistent hyperexcitability of neurons in the central nervous system (CNS). The aim of this study was to evaluate the cutaneous neural sensory perception in the RPA in patients with chronic postcholecystectomy biliary pain and a sphincter of Oddi (SO) dysfunction (SOD). Forty-two patients with persistent biliary pain and suspected SOD, 27 age-matched healthy volunteers, and 18 age-matched asymptomatic cholecystectomized controls were prospectively investigated by quantitative sensory testing (Neurometer CPT). The biliary symptoms and the severity of pain were classified on a visual analog pain severity scale system via a previously validated and standardized questionnaire. The patients helped the doctors locate the RPA in the right upper quadrant. The sensory detection threshold was determined noninvasively (Neurometer CPT) with transcutaneous electrical stimulation at 5, 250, and 2,000 Hz, and different current intensities (range from 0.01 to 9.99 mA) applied in a single (patient) blinded method. These three frequencies selectively excite small unmyelinated (C fibers), small myelinated (A-delta), and large myelinated (A-beta) fibers, which transmit dull pain, sharp pain, and touch, respectively. The contralateral region of the abdomen left upper quadrant served as the control area. The sensory current perception threshold ratio (SCPTR) of the data measured in the contralateral area and the RPA was calculated. The SCPTRs in the definite SOD patients with biliary pain, healthy volunteers, the asymptomatic cholecystectomized controls, and the symptomatic cholecystectomized patients but without SOD were 2.32 +/- 1.4 versus 1.06 +/- 0.24 versus 0.97 +/- 0.16 versus 0.83 +/- 0.35 at 2,000 Hz; 2.19 +/- 1.0 versus 1.01 +/- 0.26 versus 1.02 +/- 0.25 versus 0.88 +/- 0.35 at 250 Hz; and 2.19 +/- 1.1 versus 1.12 +/- 0.26 versus 0.99 +/- 0.37 versus 0.84 +/- 0.32 at 5 Hz, respectively. Significant hypersensitivity was detected in the RPA at different stimulation frequencies in the SOD patients with biliary pain versus the cholecystectomized controls: at 5 Hz: P = 0.00001; at 250 Hz: P = 0.00001; and at 2,000 Hz: P = 0.0001, respectively. Continuous visceral pain (biliary pain) caused by local inflammatory/sensitizing processes or a CNS malfunction could lead to significant hypersensitivity of the peripheral nociceptive nerve fibers in SOD patients. Postcholecystectomy pain may be explained by persistent hyperexcitability of the nociceptive neurons in the CNS with or without objective motility disorders of the SO.

Endogenous Tumor Necrosis Factor α (TNFα) Requires TNF Receptor Type 2 to Generate Heat Hyperalgesia in a Mouse Cancer Model

To provide a tool to investigate the mechanisms inducing and maintaining cancer-related pain and hyperalgesia, a soft tissue tumor/metastasis model was developed that is applicable in C57BL/6J wild-type and transgenic mice. We show that the experimental tumor-induced heat hyperalgesia and nociceptor sensitization were prevented by systemic treatment with the tumor necrosis factor alpha (TNFalpha) antagonist etanercept. In naive mice, exogenous TNFalpha evoked heat hyperalgesia in vivo and sensitized nociceptive nerve fibers to heat in vitro. TNFalpha enhanced the expression of the nociceptor-specific heat transducer ion channel transient receptor potential vanilloid 1 (TRPV1) and increased the amplitudes of capsaicin and heat-activated ionic currents via p38/MAP (mitogen-activated protein) kinase and PKC (protein kinase C). Deletion of the tumor necrosis factor receptor type 2 (TNFR2) gene attenuated heat hyperalgesia and prevented TRPV1 upregulation in tumor-bearing mice, whereas TNFR1 gene deletion played a minor role. We propose endogenous TNFalpha as a key player in cancer-related heat hyperalgesia and nociceptor sensitization that generates TRPV1 upregulation and sensitization via TNFR2.

GTP up‐regulated persistent Na+ current and enhanced nociceptor excitability require NaV1.9

Persistent tetrodotoxin-resistant (TTX-r) sodium currents up-regulated by intracellular GTP have been invoked as the site of action of peripheral inflammatory mediators that lower pain thresholds, and ascribed to the Na(V)1.9 sodium channel. Here we describe the properties of a global knock-out of Na(V)1.9 produced by replacing exons 4 and 5 in SCN11A with a neomycin resistance cassette, deleting the domain 1 voltage sensor and introducing a frameshift mutation. Recordings from small (< 25 microm apparent diameter) sensory neurones indicated that channel loss eliminates a TTX-r persistent current. Intracellular dialysis of GTP-gamma-S did not cause an up-regulation of persistent Na(+) current in Na(V)1.9-null neurones and the concomitant negative shift in voltage-threshold seen in wild-type and heterozygous neurones. Heterologous hNa(V)1.9 expression in Na(V)1.9 knock-out sensory neurones confirms that the human clone can restore the persistent Na(+) current. Taken together, these findings demonstrate that Na(V)1.9 underlies the G-protein pathway-regulated TTX-r persistent Na(+) current in small diameter sensory neurones that may drive spontaneous discharge in nociceptive nerve fibres during inflammation.

Neuronal modulation of lung injury induced by polymeric hexamethylene diisocyanate in mice

1,6-Hexamethylene diisocyanate biuret trimer (HDI-BT) is a nonvolatile isocyanate that is a component of polyurethane spray paints. HDI-BT is a potent irritant that when inhaled stimulates sensory nerves of the respiratory tract. The role of sensory nerves in modulating lung injury following inhalation of HDI-BT was assessed in genetically manipulated mice with altered innervation of the lung. Knockout mice with a mutation in the low-affinity nerve growth factor receptor (NGFR), which have decreased innervation by nociceptive nerve fibers, and transgenic mice expressing nerve growth factor (NGF) from the lung-specific Clara cell secretory protein (CCSP) promoter, which have increased innervation of the airways, were exposed to HDI-BT aerosol and evaluated at various times after exposure. NGFR knockout mice exhibited significantly more, and CCSP-NGF transgenic mice exhibited significantly less injury and inflammation compared with wild-type mice, indicative of a protective effect of nociceptive nerves on the lung following HDI-BT inhalation. Transgenic mice overexpressing the tachykinin 1 receptor (Tacr1) in lung epithelial cells also showed less severe injury and inflammation compared with wild-type mice after HDI-BT exposure, establishing a role for released tachykinins acting through Tacr1 in mediating at least part of the protective effect. Treatment of lung fragments from Tacr1 transgenic mice with the Tacr1 ligand substance P resulted in increased cAMP accumulation, suggesting this compound as a possible signaling mediator of protective effects on the lung following nociceptive nerve stimulation. The results indicate that sensory nerves acting through Tacr1 can exert protective or anti-inflammatory effects in the lung following isocyanate exposure.

Rhythm transformation in nerve fibers by local anesthetics: From biophysics of sodium channels to physiology of anesthesia

The review considers the basic stages in the study of rhythm transformation in the nerve fibers by local anesthetics and underlying use-dependent block of sodium channels. A potency of use-dependent local anesthetics to produce the rhythm transformation in nociceptive nerve fibers sufficient to attain local anesthesia without complete block of conduction was examined. A hypothesis was tested on attaining the conditions of local anesthesia by a decrease in discharge frequency of C-fiber nociceptors below the critical level separating the firing frequency in these sensors corresponding to their excitation with subnociceptive and nociceptive chemical stimuli. This critical level (about 2 Hz) was determined by comparison of the discharges in feline cutaneous C-fiber nociceptors during injection of chemical nociceptive and non-nociceptive stimuli. The discharge frequency in C-fiber nociceptors can be decreased in a use-dependent manner below the critical level by subcutaneous injection of lidocaine or N-propyl-ajmaline. The importance of use-dependent local anesthesia for preservation of trophic influences of the nervous system in the damaged tissue is discussed.

Understanding LTP in Pain Pathways

Long-term potentiation (LTP) at synapses of nociceptive nerve fibres is a proposed cellular mechanism underlying some forms of hyperalgesia. In this review fundamental properties of LTP in nociceptive pathways are described. The following topics are specifically addressed: A concise definition of LTP is given and a differentiation is made between LTP and "central sensitisation". How to (and how not to) measure and how to induce LTP in pain pathways is specified. The signal transduction pathways leading to LTP at C-fibre synapses are highlighted and means of how to pre-empt and how to reverse LTP are delineated. The potential functional roles of LTP are evaluated at the cellular level and at the behavioural level in experimental animals. Finally, the impact of LTP on the perception of pain in human subjects is discussed.

The Degenerated Lumbar Intervertebral Disc is Innervated Primarily by Peptide-Containing Sensory Nerve Fibers in Humans

Immunohistochemical study of the sensory innervation of the human lumbar intervertebral disc. To determine the type of sensory fibers innervating human degenerated lumbar intervertebral discs. Sensory neurons involved in pain perception related to inflammation in rats are typically small, peptide-containing neurons immunoreactive for calcitonin gene-related peptide (CGRP). Small non-peptide-containing neurons binding to isolectin B4 (IB4) may also be involved in pain states, such as nerve injury pain. The character of such sensory neurons in humans has not been clarified. A degenerated, painful lumbar intervertebral disc was harvested from each of 8 patients during surgery. Sections were immunostained for protein gene product 9.5 (PGP 9.5, a general neuronal marker), CGRP, and IB4. The numbers of PGP 9.5- and CGRP-immunoreactive, and IB4-binding nerve fibers in the discs were counted. PGP 9.5-immunoreactive fibers were observed in all discs. Nerve fibers immunoreactive for CGRP were also observed in 6 of 8 cases. IB4-binding nerve fibers were not found in any case. Almost all of the nociceptive nerve fibers in the human intervertebral disc are peptide-containing nerve fibers, similar to the rat disc, suggesting that nerve fibers related to inflammation may transmit pain originating from human degenerated intervertebral discs.

Central distribution of nociceptive intradental afferent nerve fibers in the rat

The central distribution of intradental afferent nerve fibers was investigated by combining electron microscopic observations with a selective method for inducing degeneration of the A delta- and C-type afferent fibers. Degenerating terminals were found on the proprioceptive mesencephalic trigeminal neurons and on dendrites in the neuropil of the trigeminal motor nucleus after application of capsaicin to the rat's lower incisor tooth pulp. The results give anatomical evidence of new sites of central projection of intradental A delta- and C-type fibers whereby the nociceptive information from the tooth pulp can affect jaw muscle activity.

Synaptic Amplifier of Inflammatory Pain in the Spinal Dorsal Horn

Inflammation and trauma lead to enhanced pain sensitivity (hyperalgesia), which is in part due to altered sensory processing in the spinal cord. The synaptic hypothesis of hyperalgesia, which postulates that hyperalgesia is induced by the activity-dependent long-term potentiation (LTP) in the spinal cord, has been challenged, because in previous studies of pain pathways, LTP was experimentally induced by nerve stimulation at high frequencies ( approximately 100 hertz). This does not, however, resemble the real low-frequency afferent barrage that occurs during inflammation. We identified a synaptic amplifier at the origin of an ascending pain pathway that is switched-on by low-level activity in nociceptive nerve fibers. This model integrates known signal transduction pathways of hyperalgesia without contradiction.

Tension-type headache as the unique pain experience of a patient with congenital insensitivity to pain

Congenital insensitivity to pain (CIP) is a rare clinical syndrome characterized by dramatic impairment of pain perception since birth and is generally caused by a hereditary sensory and autonomic neuropathy (HSAN) with loss of the small-calibre, nociceptive nerve fibres. We report the case of a 32-year-old woman with CIP and a presumptive diagnosis of HSAN type V, who experienced physical pain for the first and unique time in her life shortly after the sudden loss of her brother. This patient had sustained innumerable painless injuries during childhood, including bone fractures and severe burns. The only pain she ever felt consisted in an intense headache, which took place in a context of strong emotional overload and anxiety, 3 weeks after her younger brother died suddenly in a car accident. The description of this inaugural episode of headache fulfilled the diagnostic criteria of episodic tension-type headache. This case strongly suggests that the transcription of the grief of bereavement into physical pain may sometimes occur independently of the peripheral mechanisms of nociception and despite the lack of previous pain experience. In the light of recent experimental data showing that the same neural mechanisms that regulate physical pain may also control the expression of separation distress and the feeling of social exclusion, this unique case helps to better understand why some patients may feel physically hurt after the loss of someone they love.

Role of different proton-sensitive channels in releasing calcitonin gene-related peptide from isolated hearts of mutant mice

Calcitonin gene-related peptide (CGRP), a potent vasodilator released from a subset of sensory Adelta- and C-fiber afferents, has been suggested to play a beneficial role in myocardial ischemia. The aim of the present study was to investigate some receptors possibly involved in the proton-mediated CGRP release from the heart. CGRP release from freshly isolated hearts of mice lacking the capsaicin receptor (TRPV1-/-), the bradykinin receptor type 2 (B2-/-), or the acid-sensing ion channel type 3 (ASIC3-/-) and their wild-type littermates (TRPV1+/+, B2+/+, ASIC3+/+) were compared. Hearts were passed through a series of solutions based on oxygenated synthetic interstitial fluid (SIF). SIF buffered to pH 5.7 or 5.2 was used as an acidic test stimulus, and capsaicin (5x10(-7) M) was finally applied as a positive control. All eluates were processed using an enzyme immunoassay (EIA) for measurement of CGRP concentrations. SIF at pH 5.7 and 5.2 caused significant increases in CGRP release in TRPV1+/+ but not in mice lacking the TRPV1 receptor. The same acid stimuli caused no significant differences in CGRP release between ASIC3+/+ and ASIC3-/- or between B2+/+ and B2-/-, respectively. Capsaicin caused massive CGRP release in all mouse genotypes with the exception of TRPV1-/-. We conclude that cardiac acidosis is a strong stimulus to release CGRP from the mouse heart. This effect seems to be primarily mediated through activation of TRPV1 receptors that are known to be expressed by slowly conducting nociceptive primary afferent nerve fibers.

Common cortical network for first and second pain

We measured, with whole-scalp magnetoencephalography, evoked fields from 10 healthy subjects to 1-ms thulium-laser stimuli that selectively activated nociceptive nerve fibers. The stimuli were delivered to the dorsum of the subject's left hand. The earliest cortical responses peaked at 165 ± 7 ms, agreeing with the conduction velocity of Aδ-fibers. To stimulate unmyelinated C-fibers, we modified the method of Bragard et al. [Bragard, D., Chen, A.C., Plaghki, L., 1996. Direct isolation of ultra-late (C-fibre) evoked brain potentials by CO 2 laser stimulation of tiny cutaneous surface areas in man. Neurosci. Lett. 209, 81–84], by decreasing the total energy of the laser beam and by restricting the size of the stimulated skin area to 0.2–0.3 mm 2. The earliest cortical responses to these stimuli peaked at 811 ± 14 ms. Bilateral activation of the SII cortices was detected in all 10 subjects to Aδ and in 8 subjects to C stimuli, emphasizing the importance of the SII cortex in processing of pain. Additional activation was observed in the posterior parietal cortex (PPC), probably related to sensorimotor coordination targeted to produce precise motor acts that reduce or prevent the pain; the PPC activation may have been accentuated by the required continuous evaluation of the perceived pain. In contrast to some earlier studies, we did not observe activation of the primary somatosensory cortex (SI). Additional activations to both types of stimuli were detected in the cingulate cortex (three subjects) and in the bilateral insular cortex (two subjects). These results implicate that the nociceptive inputs mediated by the Aδ- and C-fibers are processed in a common cortical network in different time windows. Reliable temporospatial characterization of cortical responses to first and second pain offers a unique tool for basic and clinical neuroscience to study the two distinctive pain fiber systems at cortical level.

Eine Innovation in der akuten Migränetherapie: CGRP-Rezeptorantagonisten

Neurogenic inflammation caused by the release of vasoactive neuropeptides such as calcitonin gene-related peptide (CGRP) from nociceptive perivascular nerve fibres has been implicated in the development of acute migraine pain. It has recently been demonstrated that the CGRP receptor antagonist BIBN 4096 BS significantly reduces acute pain in migraine. This therapeutic efficacy provides further evidence for a critical role of CGRP in the pathophysiology of migraine. Given the apparent absence of vasoconstrictor activity both in meningeal and extracranial vessels, BIBN 4096 BS may provide an alternative for the treatment of migraine in those patients where triptans and ergotamine derivatives are contraindicated due to their side effects.

Reduced heat sensitivity and epidermal nerve fiber immunostaining following single applications of a high-concentration capsaicin patch

Capsaicin-containing plant extracts have been used as topical treatments for a variety of pain syndromes for many centuries. Current products containing capsaicin in low concentrations (usually 0.025–0.075% w/w) have shown efficacy against a variety of pain conditions in clinical studies. However, in order to produce significant analgesic effects, these formulations require frequent re-dosing, often as much as three to five times daily for several weeks. Previous functional and immunohistochemical studies following prolonged exposures to low-concentration capsaicin cream suggested that the duration and onset of analgesic efficacy correlate with a reduction of cutaneous nociceptive sensory nerve fiber responsiveness and immunostaining. The purpose of the present study was to determine whether a single topical application of a high-concentration capsaicin-containing (8% w/w) patch for 120 min or less would induce similar effects on cutaneous nociceptive nerve fibers. Seven days following patch application, changes in heat and cold perception thresholds were determined by quantitative sensory testing and punch biopsies were collected to assess epidermal nerve fiber (ENF) immunostaining density at the application site using PGP 9.5 as a marker. The results show a significant reduction of heat, but not cold, sensitivity and reduction of ENF immunostaining with high-capsaicin concentration patch applications for 60 or 120 min, compared to placebo patch applications. Application sites exposed to low-capsaicin concentration (0.04% w/w) patches for 120 min or high-concentration patches for 30 min were not significantly different from placebo with respect to either thermal threshold detection or ENF immunostaining. The ability of a single 60 min high-concentration patch application to mimic effects produced by prolonged exposure to low-concentration capsaicin creams suggests a new approach to the management of chronic pain syndromes.