Sensitive Afferents Research Articles

Rectal hyposensitivity: pathophysiological mechanisms

Rectal hyposensitivity (RH) relates to a diminished perception of rectal distension. It may occur due to afferent nerve dysfunction and/or secondary to abnormal structural or biomechanical properties of the rectum. The aim of this study was to determine the contribution of these underlying pathophysiological mechanisms by systematically evaluating rectal diameter, compliance and afferent nerve sensitivity in patients with RH, using methodology employed in clinical practice. The study population comprised 45 (33 women; median age 48, range 25-72 years) constipated patients (Rome II criteria) with RH and 20 with normal rectal sensitivity on balloon distension and 20 healthy volunteers. Rectal diameter was measured at minimum distending pressure during isobaric distension under fluoroscopic screening. Rectal compliance was assessed during phasic isobaric distension by measuring the slope of the pressure-volume curve. Electrical stimulation of the rectal mucosa was employed to determine afferent nerve function. Values were compared to normal ranges established in healthy volunteers. The upper limits of normal for rectal diameter, compliance and electrosensitivity were 6.3 cm, 17.9 mL mmHg(-1) and 21.3 mA respectively. Among patients with RH, rectal diameter, but not compliance, was increased above the normal range (megarectum) in seven patients (16%), two of whom had elevated electrosensitivity thresholds. Rectal diameter and compliance were elevated in 23 patients (51%), nine of whom had elevated electrosensitivity thresholds. The remaining 15 patients (33%) with RH had normal rectal compliance and diameter, all of whom had elevated electrosensitivity thresholds. Two-third of the patients with RH on simple balloon distension have elevated rectal compliance and/or diameter, suggesting that impaired perception of rectal distension is due to inadequate stimulation of the rectal afferent pathway. However, a proportion of such patients also appear to have impaired nerve function. In the remaining one-third of the patients, rectal diameter and compliance are normal, while electrosensitivity thresholds are elevated, suggestive of true impaired afferent nerve function. Identification of these subgroups of patients with RH may have implications regarding their management.

Electrophysiological Properties of Dural Afferents in the Absence and Presence of Inflammatory Mediators

Migraine is a debilitating condition characterized by recurrent severe head pain. Although mechanisms underlying a migraine attack remain controversial, one proposal is that inflammatory mediator (IM)-induced activation and sensitization of dural afferents contribute to the initiation of migraine pain. We and others have shown that the electrophysiological properties of afferents, both in the absence and the presence of IM, vary as a function of target of innervation. These differences may account for unique aspects of pain syndromes associated with specific body regions. Therefore the purpose of the present study was to test the hypothesis that the electrophysiological properties of dural afferents differ from those innervating the temporalis muscle (TM), a structure in close proximity to the dura but that is not associated with pain syndromes at all similar to migraine. Acutely dissociated retrograde labeled primary afferents innervating the dura and TM were examined with whole cell current-clamp recordings. Passive and active electrophysiological properties were determined before and after the application of IM: (in muM) prostaglandin E(2) (1), bradykinin (10), and histamine (1). In the absence of IM, there were significant differences between the two populations, particularly with respect to the response to suprathreshold stimulation where dural afferents were more excitable than TM afferents. Importantly, although both populations of afferents were sensitized by IM, the pattern of passive and active electrophysiological changes associated with IM-induced sensitization of these two populations of afferents suggested that there were both similarities and marked differences between the two with respect to underlying mechanisms of sensitization. If the differences between dural and TM afferents are due to a differential pattern of ion channel expression rather than differences in the relative density/biophysical properties of the same ion channels, it may be possible to selectively treat migraine pain by targeting the distinct mechanisms underlying IM-induced sensitization of dural afferents.

Contribution of muscle afferent activation to the anterior cerebral artery blood velocity response to calf exercise in humans

It has been proposed that the activation of mechanically sensitive muscle afferents (muscle mechanoreflex) is important for exercise‐induced increases in regional cerebral blood flow. To examine this possibility, and to assess how regional cerebral blood flow is influenced by activation of metabolically sensitive muscle afferents (muscle metaboreflex) and central signals arising from higher centers (central command), 12 subjects performed voluntary (Vol Ex) and electrically stimulated (Stim Ex) rhythmic calf exercise at 35% of maximum voluntary contraction, followed by post exercise muscle ischemia (PEMI). Anterior cerebral artery blood velocity (ACAVmean), mean arterial pressure (MAP), and end‐tidal PCO2 were measured throughout. Exercise induced increases in MAP were similar during Vol Ex (Δ6±2 mmHg) and Stim Ex (Δ7±2 mmHg; P>0.05). ACAVmean was increased from rest during Vol Ex (Δ15±1%; P<0.05), but remained unchanged during Stim Ex (P>0.05). MAP remained elevated during PEMI following both Vol Ex and Stim Ex (P<0.05 vs. rest), while ACAVmean was not different from rest (P>0.05). End‐tidal PCO2 was unchanged from rest throughout. These data suggest that selective activation of skeletal muscle afferents (i.e. Stim Ex or PEMI) does not increase ACAVmean, and that increases in ACAVmean during volitional contraction of an exercising calf muscle are dependent upon the presence of central command.

Facilitatory Interactions between 5‐HT and Thromboxane A2 in Stimulation of Ischemically Sensitive Cardiac Sympathetic Afferents

We have demonstrated that the endogenously produced mediators serotonin (5‐HT) and thromboxane A2 (TxA2) contribute to activation of cardiac afferents during ischemia. In the present study we hypothesized facilitatory interactions between these two metabolites in stimulation of cardiac afferents during ischemia. Nerve activity of single cardiac afferent units was recorded from the left sympathetic chain or rami communicantes (T2 ‐ T5) of anesthetized cats. Twenty ischemically sensitive afferents (CV= 0.28 ‐ 3.62 m/s, 4 Ad‐ and 16 C‐fibers) were identified. We observed that a repeat injection of 5‐HT (40 μg/kg) into left atrium (LA), 4 min after LA 2.5 μg of U46619, a TxA2 mimetic, induced a significantly larger cardiac afferent response than the first 5‐HT response (0.46±0.08 to 1.06±0.11 vs.0.45±0.13 to 1.90±0.18 imp/s, first vs. second injection, n=3). In a control group, repeated 5‐HT (40 μg/kg, LA) evoked consistent responses in three other ischemically sensitive afferents. Furthermore, LA administration of 5‐HT (40 μg/kg) and U46619 (2.5 μg) caused a larger response than simple addition of the individual responses (n=5). Additionally, the responses of three cardiac afferents to repeat U46619 (2.5 μg, LA) were enhanced compared with the U46619 response before 5‐HT, while the responses of three other cardiac afferents to repeated U46619 stimulation were consistent. Finally, blockade of the 5‐HT3 receptors with tropisetron (200 μg/kg, iv) attenuated the responses of three cardiac afferent to U46619 (2.5 μg, LA) by 52%. These preliminary data suggest that 5‐HT and TxA2 each facilitate the responses of ischemically sensitive cardiac afferent endings to the actions of other metabolite (Supported by NIH HL66217).

Sensitization of capsaicin-sensitive lung vagal afferents by anandamide in rats: role of transient receptor potential vanilloid 1 receptors

Anandamide (AEA), an arachidonic acid derivative produced during inflammatory conditions, is an endogenous agonist of both transient receptor potential vanilloid 1 (TRPV1) receptors and cannabinoid CB1 receptors. Sensitization of capsaicin-sensitive lung vagal afferent (CSLVA) fibers by chemical mediators is important in the pathogenesis of hyperreactive airway diseases. We investigated the effect of the intravenous infusion of AEA (2 mg x kg(-1) x ml(-1), 0.5 ml/min for 2 min) on the sensitivity of CSLVA fibers to chemical and mechanical stimulation in anesthetized rats. In artificially ventilated rats, AEA infusion only mildly elevated the baseline activity of CSLVA fibers. However, CSLVA fiber responses to right atrial injection of capsaicin, AEA, or adenosine and to lung inflation (tracheal pressure = 30 cmH(2)O) were all markedly potentiated during AEA infusion, which reverted 20 min after termination of the infusion. The potentiating effect on the sensitivity of CSLVA fibers to adenosine injection or lung inflation was completely blocked by pretreatment with capsazepine (a TRPV1 receptor antagonist) but was unaffected by pretreatment with AM281 (a CB1 receptor antagonist). In spontaneously breathing rats, right atrial injection of adenosine evoked an apneic response that is presumably mediated through CSLVA fibers. Similarly, the adenosine-evoked apneic response was potentiated during AEA infusion, and this potentiating effect was also completely prevented by pretreatment with capsazepine. These results suggest that AEA infusion at the dose tested produces a mild activation of TRPV1 receptors and this nonspecifically increases CSLVA fiber sensitivity to chemical and mechanical stimulation.

Post-inflammatory colonic afferent sensitisation: different subtypes, different pathways and different time courses

Objective:Intestinal infection evokes hypersensitivity in a subgroup of patients with irritable bowel syndrome (IBS) long after healing of the initial injury. Trinitrobenzene sulfonic acid (TNBS)-induced colitis in rodents likewise results...

A novel herbal preparation desensitizes mesenteric afferents to bradykinin in the rat small intestine

Herbal preparations are evolving as promising agents for the treatment of functional gastrointestinal disorders which are considered to be secondary to visceral hypersensitivity. We aimed to determine whether a new combination of six herbal extracts reduces the sensitivity of intestinal afferents in rat. Male Wistar rats (250-350 g, n = 6 per group) were gavaged with either vehicle or 2.5, 5 or 10 mL kg(-1) of STW 5-II, a herbal preparation which contains six extracts. Two hours later, animals were anaesthetized and extracellular multi-unit mesenteric afferent nerve recordings were obtained in the proximal jejunum in vivo. Afferent discharge to 5-hydroxy-tryptamine (5-HT) (5, 10, 20 and 40 microg kg(-1), i.v.), luminal distension (0-60 mmHg) and bradykinin (BK) (15, 30 and 60 microg kg(-1), i.v.) was recorded. At baseline, spontaneous afferent discharge was not different following pretreatment with the various doses of STW 5-II compared with vehicle. The pressure-dependent increase in afferent discharge to intraluminal ramp distension and the dose-dependent increase in afferent firing following 5-HT were also uninfluenced by STW 5-II pretreatment. In contrast, the afferent nerve responses to 15, 30 and 60 microg kg(-1) of BK were reduced following 10 mL kg(-1) STW 5-II with peaks at 106 +/- 19, 153 +/- 22 and 156 +/- 25 imp s(-1) compared with 160 +/- 15, 228 +/- 14 and 220 +/- 16 imp s(-1) following vehicle pretreatment (mean +/- SEM, P < 0.05). Intestinal afferent sensitivity to BK which plays a prime role in nociception was reduced following STW 5-II. Thus, STW 5-II may be of therapeutic use for conditions that involve neuronal hypersensitivity and the release of BK in the intestine.

Afferent nerve sensitivity is decreased by an iNOS‐dependent mechanism during indomethacin‐induced inflammation in the murine jejunum in vitro

Evidence exists that visceral afferent sensitivity is subject to regulatory mechanisms. We hypothesized that afferent sensitivity is decreased in the small intestine during intestinal inflammation by an inducible nitric oxide synthase (iNOS)-dependent mechanism. C57BL/6 mice were injected twice with vehicle or 60 mg kg(-1) indomethacin subcutaneously to induce intestinal inflammation. Afferent sensitivity was recorded on day 3 from a 2-cm segment of jejunum in vitro by extracellular multi-unit afferent recordings from the mesenteric nerve bundle. In subgroups (n = 6), iNOS was inhibited selectively by L-N6-(1-iminoethyl)-lysine (L-NIL) given either chronically from day 1-3 (3 mg kg(-1) twice daily i.p.) or acutely into the organ bath (30 micromol L(-1)). The indomethacin-induced increase of macroscopic and microscopic scores of intestinal inflammation (both P < 0.05) were unchanged after pretreatment with L-NIL. Peak afferent firing following bradykinin (0.5 micromol L(-1)) was 55 +/- 8 impulse s(-1) during inflammation vs 97 +/- 7 impulse s(-1) in controls (P < 0.05). Normal firing rate was preserved following L-NIL pretreatment (112 +/- 16 impulse s(-1)) or acute administration of L-NIL (108 +/- 14 impulse s(-1)). A similar L-NIL dependent reduction was observed for 5-HT (250 micromol L(-1)) and mechanical ramp distension from 20 to 60 cmH(2)O (both P < 0.05). Intraluminal pressure peaks were decreased to 0.66 +/- 0.1 cmH(2)O during inflammation compared to 2.51 +/- 0.3 in controls (P < 0.01). Afferent sensitivity is decreased by an iNOS-dependent mechanism during intestinal inflammation which appears to be independent of the inflammatory response. This suggests that iNOS-dependent nitric oxide production alters afferent sensitivity during inflammation by interfering with signal transduction to afferent nerves rather than by attenuating intestinal inflammation.

The Role of Fingerprints in the Coding of Tactile Information Probed with a Biomimetic Sensor

In humans, the tactile perception of fine textures (spatial scale <200 micrometers) is mediated by skin vibrations generated as the finger scans the surface. To establish the relationship between texture characteristics and subcutaneous vibrations, a biomimetic tactile sensor has been designed whose dimensions match those of the fingertip. When the sensor surface is patterned with parallel ridges mimicking the fingerprints, the spectrum of vibrations elicited by randomly textured substrates is dominated by one frequency set by the ratio of the scanning speed to the interridge distance. For human touch, this frequency falls within the optimal range of sensitivity of Pacinian afferents, which mediate the coding of fine textures. Thus, fingerprints may perform spectral selection and amplification of tactile information that facilitate its processing by specific mechanoreceptors.

Increased pain from muscle fascia following eccentric exercise: animal and human findings

Mechanisms and structures which are involved in eccentric exercise-induced delayed onset muscle soreness (DOMS) are not yet clarified. Tissue and site specificity may be important considerations in afferent sensitisation following eccentric exercise. This study investigated the nociceptive response to hypertonic sodium solution applied to fascial/epimysium tissue and mechanically sensitised sites in muscle by assessing (1) afferent recordings in animals and (2) psychophysical assessment in humans. Seventeen male rats underwent eccentric contraction of extensor digitorum longus muscle, while 11 rats served as an unexercised naïve group. Two days post-exercise, group IV afferent fibre activity was recorded in response to superfusion of hypertonic Krebs solution on the mechanically sensitised muscle/epimysium site. Mechanical sensitisation was confirmed with significant increases in afferent response and decreases in threshold to mechanical stimulation in the eccentrically exercised rats compared to naïve rats. There was no difference in afferent response magnitude to hypertonic Krebs solution between exercise and naïve groups. In the human study, 13 volunteers participated. After bilateral assessment of pressure pain thresholds (PPT) along the tibialis anterior muscles, eccentric exercise was performed to induce DOMS in m. tibialis anterior of one leg. Site of maximal mechanical sensitivity was identified 24 h later and injected with hypertonic saline at fascial and deep muscle levels. The corresponding site on the opposite unexercised leg served as a control. Fascial injection of the exercised muscle caused significantly higher pain intensity compared to all other injections. Response to deep muscle stimulation was not different between sides. This suggests that fascia rather than muscle tissue is important in DOMS associated sensitisation.

Mechanisms of eosinophil major basic protein-induced hyperexcitability of vagal pulmonary chemosensitive neurons

We have reported recently that eosinophil-derived basic proteins directly enhance the capsaicin- and electrical stimulation-evoked whole cell responses in rat pulmonary sensory neurons (19). Our present study further elucidates the mechanisms underlying the sensitization of pulmonary afferent nerves induced by these cationic proteins. Our results show that pretreatment with eosinophil major basic protein (MBP; 2 microM, 60 s) significantly enhanced the excitability of isolated rat vagal pulmonary chemosensitive neurons to acid and ATP in the current-clamp mode, but this potentiating effect was absent in the voltage-clamp recordings. The hyperexcitability induced by MBP was not prevented by the blockade of either transient receptor potential vanilloid type-1 receptor (TRPV1) selectively (inhibitor: AMG 9810; 1 microM, 2 min) or all TRPV1-4 channels (inhibitor: ruthenium red; 5 microM, 2 min). In addition, MBP also markedly potentiated the excitability of mouse pulmonary chemosensitive neurons, and no detectable difference was found between those isolated from wild-type and TRPV1 knockout mice. Furthermore, MBP pretreatment affected the decay time and recovery phase of the action potentials evoked by current injections and significantly inhibited both the sustained delayed-rectifier voltage-gated K(+) current (IK(dr)) and the A-type, fast-inactivating K(+) current (IK(a)) in these sensory neurons. In conclusion, our results indicate that the inhibition of IK(dr) and IK(a) should, at least in part, account for the hyperexcitability of pulmonary chemosensitive neurons induced by eosinophil-derived cationic proteins, whereas an interaction with TRPV1 channels does not seem to be required for the sensitizing effect of these proteins.

Intestinal Afferent Nerve Sensitivity is Increased During the Initial Development of Postoperative Ileus in Mice

IntroductionNeuronal reflex inhibition of gastrointestinal motility is a key mechanism in the development of postoperative ileus (POI). The aim of our study was to determine whether intestinal afferent nerve fibers are sensitized during the first hours after surgery contributing to this mechanism. MethodsUnder enflurane anesthesia, C57BL/6 mice underwent laparotomy followed by sham treatment or standardized small bowel manipulation to induce POI. After 1, 3, or 9 h, extracellular multi-unit mesenteric afferent nerve recordings were performed in vitro from 2 cm segments of jejunum (subgroups n = 6) superfused with Kreb’s buffer (32°C, gassed with O2/CO2 mixture). Segments were cannulated to monitor luminal pressure and intestinal motility. Afferent impulses as response to bradykinin (0.5 μM) and to mechanical ramp distension of the intestinal lumen from 0 to 80 cmH2O were recorded. ResultsAt 1 h, amplitudes of intestinal contractions were 0.8±0.2 cmH2O after induction of POI and 5.0±0.8 cmH2O in sham controls (mean ± SEM; p < 0.01). A similar difference was observed for segments harvested at 3 and 9 h. Afferent firing to serosal bradykinin was increased at 1, 3, and 9 h in POI segments compared to sham controls (p < 0.05 at 1 h, p < 0.01 at 3 and 9 h). During distension with high pressures, afferent firing rate was increased at 1 and 3 h in segments after induction of POI compared to sham controls. Nine hours postoperatively, contracted and dilated segments were observed during POI that were investigated separately. While afferent firing in dilated segments was increased to 176 ± 16 imp s−1 at 80 cmH2O luminal distension (p < 0.01), it was 46 ± 5 imp s−1 in contracted segments (p < 0.001) compared to 77 ± 4 imp s−1 in sham controls. ConclusionsAfferent firing to bradykinin and high threshold distension is augmented in the early phase of POI. As these stimuli are known to sensitize predominantly spinal afferents, this mechanism may contribute to reflex inhibition of intestinal motility during POI.

Aging reduced mechanical sensitivity of unmyelinated afferents electrically identified in the rat skin-saphenous nerve preparations in vitro

Aging reduced mechanical sensitivity of unmyelinated afferents electrically identified in the rat skin-saphenous nerve preparations in vitro

Cough and gastroesophageal reflux: Insights from animal models

Chronic cough in gastroesophageal reflux disease (GERD) has been attributed to irritation of the esophagus and/or upper airways by reflux of gastric content. Animal models have provided insight into both of these putative mechanisms. In patients with chronic cough and GERD, stimuli associated with reflex in the esophagus sensitize the cough reflex. This sensitization can be reproduced in the guinea pig and is most likely mediated by the esophageal afferent nerve fibers carried by the vagus nerves. Studies in animals have identified several subtypes of vagal esophageal C-fibers that may subserve this function. The putative nociceptive vagal C-fibers in the guinea pig esophagus are stimulated by acid and express the TRPV1 and TRPA1 receptors that confer responsiveness to disparate noxious stimuli. Acute and/or chronic irritation of the upper airways by reflux may contribute to cough by stimulation and/or sensitization of the airway afferent nerves. Studies in animals have identified airway nerves that likely initiate cough due to aspirated reflux; have characterized their pharmacology; and have provided insight into changes of their sensitivity. Studies in animal models have also described the neurophysiology of reflexes that protect the airways from reflux. In conclusion, animal models provide mechanistic insight into the modulation of cough from the esophagus and the pharmacology of neural pathways mediating cough in GERD.

Divergent peripheral effects of pituitary adenylate cyclase-activating polypeptide-38 on nociception in rats and mice

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and its receptors have been shown in the spinal dorsal horn, on capsaicin-sensitive sensory neurons and inflammatory cells. The role of PACAP in central pain transmission is controversial, and no data are available on its function in peripheral nociception. Therefore, the aim of the present study was to analyze the effects of locally or systemically administered PACAP-38 on nocifensive behaviors, inflammatory/neuropathic hyperalgesia and afferent firing. Intraplantar PACAP-38 (0.2nmol) injection inhibited carrageenan-evoked inflammatory mechanical allodynia, mild heat injury-induced thermal hyperalgesia, as well as nocifensive behaviors in the early and late phases of the formalin test in rats. However, the above dose did not alter basal mechanical or heat thresholds. In mice, PACAP-38 (0.2nmol/kg s.c.) significantly diminished acetic acid-induced abdominal contractions, but exerted no effect on sciatic nerve ligation-induced neuropathic mechanical hyperalgesia. In contrast, local PACAP-38 injection markedly increased rotation-induced afferent firing in the inflamed rat knee joint clearly demonstrating a peripheral sensitization in this organ. These actions were blocked by VPAC1/VPAC2 receptor antagonist pretreatment, but were not altered by PAC1 receptor antagonism. This paper presents the first data for the peripheral actions of PACAP-38 on nociceptive transmission mediated by VPAC receptors. These effects seem to be divergent depending on the mechanisms of nociceptor activation and the targets of PACAP actions. In acute somatic and visceral inflammatory pain models, PACAP exerts anti-nociceptive, anti-hyperalgesic and anti-allodynic effects. It has no significant peripheral role in traumatic mononeuropathy, but induces mechanical sensitization of knee joint primary afferents.

Glutamate and capsaicin effects on trigeminal nociception II: Activation and central sensitization in brainstem neurons with deep craniofacial afferent input

We examined the effect of the peripheral application of glutamate and capsaicin to the temporomandibular joint (TMJ) in influencing the activation and central sensitization of TMJ-responsive nociceptive neurons in the trigeminal subnucleus caudalis/upper cervical cord (Vc/UCC). The activity of single neurons activated by noxious mechanical stimulation of the TMJ was recorded in the Vc/UCC of 49 halothane-anesthetized male rats. Cutaneous mechanoreceptive field (RF), cutaneous mechanical activation threshold (MAT), and TMJ MAT of each neuron were assessed before and after injection of 0.5 M glutamate (or vehicle) and 1% capsaicin (or vehicle) into the TMJ. A total of 49 nociceptive neurons (37 nociceptive-specific, 12 wide-dynamic-range) that could be activated by blunt noxious mechanical stimulation of the TMJ were studied. When injected alone, glutamate and capsaicin activated and induced central sensitization (reflected in cutaneous RF expansion and cutaneous and/or TMJ MAT reduction) in most Vc/UCC neurons. Following glutamate injection, capsaicin evoked greater activity and less cutaneous/TMJ MAT reduction compared with capsaicin alone, whereas capsaicin abolished all subsequent glutamate-evoked activity and depressed cutaneous RF expansion in most neurons. Glutamate effects on deep afferents and Vc/UCC neurons were analogous since glutamate sensitized afferent and neuronal responses to capsaicin but the desensitizing effects of capsaicin on glutamate-evoked excitability of Vc/UCC neurons contrast with the lack of capsaicin-induced modulation of glutamate-evoked afferent excitability [ Lam, D.K., Sessle, B.J., Hu, J.W., 2008a. Glutamate and capsaicin effects on trigeminal nociception I: activation and peripheral sensitization of deep craniofacial nociceptive afferents. Brain Res. doi:10.1016/j.brainres.2008.11.029], suggesting that peripheral and central sensitization may be differentially involved in the nociceptive effects of glutamate and capsaicin applied to deep craniofacial tissues.

Degranulated mast cells in the skin of adults with self-injurious behavior and neurodevelopmental disorders

The role of nociceptive processes in relation to chronic, tissue-damaging self-injury among individuals with neurodevelopmental disorders is poorly understood. Scientific investigation has been limited, in part, by the clinical reality that the majority of individuals with severe intellectual impairments have co-morbid communicative impairments making it difficult to ascertain information regarding pain. Recently, we found abnormal patterns of peripheral epidermal nerve fiber (ENF) innervation and increased neuropeptide (substance P; SP) content among a subset of individuals with chronic self-injury. Here, we provide initial evidence for peripheral neuro-immune activity specific to self-injury. Skin samples from non-injury body-matched sites were compared between non-verbal adults with and without self-injury matched on gender and disability level. Relative to disability-matched controls, individuals with chronic self-injury had significantly more degranulated mast cells and were more responsive to tactile stimulation during a sensory testing procedure. Thus, nociceptive mechanisms and peripheral afferent sensitization may play a part in mediating and maintaining chronic self-injury.

Glutamate and capsaicin effects on trigeminal nociception I: Activation and peripheral sensitization of deep craniofacial nociceptive afferents

We have examined the effect of the peripheral application of glutamate and capsaicin to deep craniofacial tissues in influencing the activation and peripheral sensitization of deep craniofacial nociceptive afferents. The activity of single trigeminal nociceptive afferents with receptive fields in deep craniofacial tissues were recorded extracellularly in 55 halothane-anesthetized rats. The mechanical activation threshold (MAT) of each afferent was assessed before and after injection of 0.5 M glutamate (or vehicle) and 1% capsaicin (or vehicle) into the receptive field. A total of 68 afferents that could be activated by blunt noxious mechanical stimulation of the deep craniofacial tissues (23 masseter, 5 temporalis, 40 temporomandibular joint) were studied. When injected alone, glutamate and capsaicin activated and induced peripheral sensitization reflected as MAT reduction in many afferents. Following glutamate injection, capsaicin-evoked activity was greater than that evoked by capsaicin alone, whereas following capsaicin injection, glutamate-evoked responses were similar to glutamate alone. These findings indicate that peripheral application of glutamate or capsaicin may activate or induce peripheral sensitization in a subpopulation of trigeminal nociceptive afferents innervating deep craniofacial tissues, as reflected in changes in MAT and other afferent response properties. The data further suggest that peripheral glutamate and capsaicin receptor mechanisms may interact to modulate the activation and peripheral sensitization in some deep craniofacial nociceptive afferents.

Trpv1 mediates spontaneous firing and heat sensitization of cutaneous primary afferents after plantar incision

TrpV1, the receptor for capsaicin, contributes to nociception in animals but appears to be much more important for signaling increased behavioral sensitivity in the injured state. The current study examined the relationship between the marked reduction in heat hyperalgesia after incision in TrpV1 knockout (KO) mice and the activity of the nociceptors in these same mice. Also, the role of TrpV1 in spontaneous activity (SA) of afferents after incision was examined. Standard teased-fiber techniques were used to record from glabrous skin afferents from incised and control TrpV1 KO and C57Bl6 mice. The loss of TrpV1 had minimal effect on the responses of mechano-heat-sensitive C-fiber afferents in the normal and incised states. However, a different group of heat sensitive afferents, termed unclassified afferents, was sensitized to heat by incision and had markedly reduced sensitization in the TrpV1 KO mice. These unclassified afferents also developed SA after incision, and generally had a lower threshold temperature compared to unclassified afferents without SA. The rate of SA was inversely correlated to the threshold temperature for heat; afferents that exhibited a higher rate of SA had a lower heat threshold. The proportion of unclassified afferents with SA was also reduced in incised TrpV1 KO mice compared to incised C57Bl6 mice. We conclude that a distinct class of afferents outside the mechano-heat-sensitive afferent population likely contributes to heat hypersensitivity after plantar incision. KO of TrpV1 influences SA in these unclassified afferents in incised skin. SA in these afferents is perhaps a manifestation of heat sensitization.

TRPV1 fans the flames of visceral pain

TRPV1 fans the flames of visceral pain