Non-nociceptive Stimuli Research Articles

Filtering out repetitive auditory stimuli in fibromyalgia: a study of P50 sensory gating.

It has been suggested that fibromyalgia (FM) patients show increased sensory processing of nociceptive and non-nociceptive stimuli and also reduced habituation. Although this pattern of increased reactivity has been established for the somatosensory modality, its generalization to other sensory modalities remains controversial. Auditory evoked potentials were obtained using a paired-stimuli paradigm from a sample of 52 FM female patients and 55 healthy women matched for age and socio-economic status. Sensory gating of the P50 component, as indicated by P50 suppression rates to the second identical stimuli, was analysed in relation to clinical indices of FM, including algometry of tender points and a number of self-reported questionnaires. Sensory gating mechanisms in FM patients proved to be normal, robust and as efficient as those recorded in control subjects. There was no correlation between P50 suppression rates and indices of clinical or experimental (threshold or tolerance) pain. In addition, P50 sensory gating was not related to the other main symptoms of FM, including fatigue, sleep dysfunction or co-morbid depression, nor to hypersensitivity to noise or headache. The results indicate that FM patients do not present significant deficits in early sensory gating when processing auditory stimuli, and therefore challenge the 'generalized hypersensitivity' hypothesis of FM.

EEG frequency tagging to dissociate the cortical responses to nociceptive and nonnociceptive stimuli.

Whether the cortical processing of nociceptive input relies on the activity of nociceptive-specific neurons or whether it relies on the activity of neurons also involved in processing nonnociceptive sensory input remains a matter of debate. Here, we combined EEG "frequency tagging" of steady-state evoked potentials (SS-EPs) with an intermodal selective attention paradigm to test whether the cortical processing of nociceptive input relies on nociceptive-specific neuronal populations that can be selectively modulated by top-down attention. Trains of nociceptive and vibrotactile stimuli (Experiment 1) and trains of nociceptive and visual stimuli (Experiment 2) were applied concomitantly to the same hand, thus eliciting nociceptive, vibrotactile, and visual SS-EPs. In each experiment, a target detection task was used to focus attention toward one of the two concurrent streams of sensory input. We found that selectively attending to nociceptive or vibrotactile somatosensory input indistinctly enhances the magnitude of nociceptive and vibrotactile SS-EPs, whereas selectively attending to nociceptive or visual input independently enhances the magnitude of the SS-EP elicited by the attended sensory input. This differential effect indicates that the processing of nociceptive input involves neuronal populations also involved in the processing of touch, but distinct from the neuronal populations involved in vision.

The sciatic nerve cuffing model of neuropathic pain in mice.

Neuropathic pain arises as a consequence of a lesion or a disease affecting the somatosensory system. This syndrome results from maladaptive changes in injured sensory neurons and along the entire nociceptive pathway within the central nervous system. It is usually chronic and challenging to treat. In order to study neuropathic pain and its treatments, different models have been developed in rodents. These models derive from known etiologies, thus reproducing peripheral nerve injuries, central injuries, and metabolic-, infectious- or chemotherapy-related neuropathies. Murine models of peripheral nerve injury often target the sciatic nerve which is easy to access and allows nociceptive tests on the hind paw. These models rely on a compression and/or a section. Here, the detailed surgery procedure for the "cuff model" of neuropathic pain in mice is described. In this model, a cuff of PE-20 polyethylene tubing of standardized length (2 mm) is unilaterally implanted around the main branch of the sciatic nerve. It induces a long-lasting mechanical allodynia, i.e., a nociceptive response to a normally non-nociceptive stimulus that can be evaluated by using von Frey filaments. Besides the detailed surgery and testing procedures, the interest of this model for the study of neuropathic pain mechanism, for the study of neuropathic pain sensory and anxiodepressive aspects, and for the study of neuropathic pain treatments are also discussed.

The Sciatic Nerve Cuffing Model of Neuropathic Pain in Mice

Neuropathic pain arises as a consequence of a lesion or a disease affecting the somatosensory system. This syndrome results from maladaptive changes in injured sensory neurons and along the entire nociceptive pathway within the central nervous system. It is usually chronic and challenging to treat. In order to study neuropathic pain and its treatments, different models have been developed in rodents. These models derive from known etiologies, thus reproducing peripheral nerve injuries, central injuries, and metabolic-, infectious- or chemotherapy-related neuropathies. Murine models of peripheral nerve injury often target the sciatic nerve which is easy to access and allows nociceptive tests on the hind paw. These models rely on a compression and/or a section. Here, the detailed surgery procedure for the "cuff model" of neuropathic pain in mice is described. In this model, a cuff of PE-20 polyethylene tubing of standardized length (2 mm) is unilaterally implanted around the main branch of the sciatic nerve. It induces a long-lasting mechanical allodynia, i.e., a nociceptive response to a normally non-nociceptive stimulus that can be evaluated by using von Frey filaments. Besides the detailed surgery and testing procedures, the interest of this model for the study of neuropathic pain mechanism, for the study of neuropathic pain sensory and anxiodepressive aspects, and for the study of neuropathic pain treatments are also discussed.

Theta Burst Stimulation Applied over Primary Motor and Somatosensory Cortices Produces Analgesia Unrelated to the Changes in Nociceptive Event-Related Potentials

Continuous theta burst stimulation (cTBS) applied over the primary motor cortex (M1) can alleviate pain although the neural basis of this effect remains largely unknown. Besides, the primary somatosensory cortex (S1) is thought to play a pivotal role in the sensori-discriminative aspects of pain perception but the analgesic effect of cTBS applied over S1 remains controversial. To investigate cTBS-induced analgesia we characterized, in two separate experiments, the effect of cTBS applied either over M1 or S1 on the event-related brain potentials (ERPs) and perception elicited by nociceptive (CO2 laser stimulation) and non-nociceptive (transcutaneous electrical stimulation) somatosensory stimuli. All stimuli were delivered to the ipsilateral and contralateral hand. We found that both cTBS applied over M1 and cTBS applied over S1 significantly reduced the percept elicited by nociceptive stimuli delivered to the contralateral hand as compared to similar stimulation of the ipsilateral hand. In contrast, cTBS did not modulate the perception of non-nociceptive stimuli. Surprisingly, this side-dependent analgesic effect of cTBS was not reflected in the amplitude modulation of nociceptive ERPs. Indeed, both nociceptive (N160, N240 and P360 waves) and late-latency non-nociceptive (N140 and P200 waves) ERPs elicited by stimulation of the contralateral and ipsilateral hands were similarly reduced after cTBS, suggesting an unspecific effect, possibly due to habituation or reduced alertness. In conclusion, cTBS applied over M1 and S1 reduces similarly the perception of nociceptive inputs originating from the contralateral hand, but this analgesic effect is not reflected in the magnitude of nociceptive ERPs.

Discriminative sensory characteristics of the lateral femoral cutaneous nerve after mepivacaine-induced block

Background and objectivesUnmyelinated C-fibres comprise the largest group of somatic afferents and have demonstrated a crucial role not only in the perception of high-threshold mechanically, thermally or chemically induced pain, but also in non-harmful low-threshold mechanical stimuli [1,2]. The objective of our study was to characterize differential sensitivity changes of C-fibre related subclasses of high-threshold and low-threshold polymodal nociceptors and low-threshold mechanoreceptors to the local anaesthetic (LA) mepivacaine during nerve block of the purely sensory lateral femoral cutaneous nerve (LFCN) in human. We assumed a diverse response of different classes of afferents to the two different concentrations of the LA mepivacaine (Scandicaine). MethodsIn a double-blind randomized experimental setting, an ultrasound-guided nerve block of the LFCN was performed in 10 healthy male subjects, each with two different concentrations of mepivacaine (0.5 and 1%). Responsiveness of afferent nerve fibres to different noxious and non-noxious stimuli was tested by Quantitative Sensory Testing (QST) 30, 180, and 300min after nerve block. Both LA concentrations of mepivacaine were compared for time course of the areas of anaesthesia for the tested sensory modalities. ResultsInitial extension of anaesthetic areas at 30min did not differ between both LA concentrations. At 180min only the anaesthetic areas to nociceptive stimuli were reduced at the site of lower mepivacaine injection (260mN: 204mm2 (18; 244; median difference and 95% confidence interval; p<0.05), heat: 276mm2 (3; 305)). In contrast, no significant differences were found between the two concentration when non-nociceptive stimuli were used (100mN: 187mm2 (4; 240), p>0.05, brush: 159mm2 (−59; 202)). ConclusionEqual initial sizes of anaesthesia areas for all sensory modalities can be explained by supramaximal perineural LA molecule concentration in both administered mepivacaine dosages. Upon washout of the LA nociceptive function is restored faster as compared to non-nociceptive sensation and higher concentration of the LA are required to maintain the analgesia. Quantitative sensory testing is able to detect different susceptibility of low threshold mechanosensors and subtypes of nociceptive C-fibres to mepivacaine. Using painful mechanical, heat and electrical stimulation different classes of nociceptors will be activated. The analgesic areas to electrical stimulation were particularly small; one might therefore hypothesize that the proposed protocol allows to also differentiate mechano-insensitive (“silent”) and mechanosensitive (“polymodal”) nociceptors. ImplicationsQST is a non-invasive method to functionally examine sensory modalities and their pharmacological modulation in humans. The method is sufficiently sensitive to differentiate the analgesic properties of mepivacaine at 0.5 and 1% and might also be adequate to different classes of nociceptors. Further development of nociceptive stimuli including supra-threshold encoding characteristics will enable to investigate peripheral analgesic effects more specifically and thus might help to design new analgesics with preferential effect on high frequency discharge of nociceptors.

Pain evaluation after a non-nociceptive stimulus in preterm infants during the first 28 days of life

BackgroundProtective mechanisms that modulate and lead to habituation to pain are immature in preterm newborn infants. AimsTo evaluate if a routine non-painful handling will be perceived as painful throughout the neonatal period in newborn infants with 28–32weeks of gestational age. Study designProspective cohort study. Subjects36 preterm infants without malformations evaluated for pain during a diaper change. Outcome measuresPatients were studied at three times (5min prior, during, and 3min after the diaper change) during five moments (72h, 7, 14, 21 and 28days of life) by evaluation of heart rate, oxygen saturation and 3 validated pain assessment tools: the Neonatal Infant Pain Scale (NIPS), the Behavioral Indicators of Infant Pain (BIIP) and Premature Infant Pain Profile (PIPP). Results were analyzed by repeated measures ANOVA adjusted for gender, gestational age at birth, number of painful procedures and use of opioids. ResultsPatients had, at birth, mean gestational age of 30.2±1.4weeks, birthweight of 1257±238g, with 50% males. Analysis of pain assessment tools did not show increase of pain presence or pain scores at the five sequential evaluation moments. The variation of oxygen saturation during the three study times was similar at the different post-natal ages, but heart rate variation increased significantly from 72h until the 28th day of life. ConclusionsIn preterm infants, the non-nociceptive handling does not trigger pain responses even after 28days of neonatal care, which includes the experience of repetitive procedural pain.

The human operculo-insular cortex is pain-preferentially but not pain-exclusively activated by trigeminal and olfactory stimuli.

Increasing evidence about the central nervous representation of pain in the brain suggests that the operculo-insular cortex is a crucial part of the pain matrix. The pain-specificity of a brain region may be tested by administering nociceptive stimuli while controlling for unspecific activations by administering non-nociceptive stimuli. We applied this paradigm to nasal chemosensation, delivering trigeminal or olfactory stimuli, to verify the pain-specificity of the operculo-insular cortex. In detail, brain activations due to intranasal stimulation induced by non-nociceptive olfactory stimuli of hydrogen sulfide (5 ppm) or vanillin (0.8 ppm) were used to mask brain activations due to somatosensory, clearly nociceptive trigeminal stimulations with gaseous carbon dioxide (75% v/v). Functional magnetic resonance (fMRI) images were recorded from 12 healthy volunteers in a 3T head scanner during stimulus administration using an event-related design. We found that significantly more activations following nociceptive than non-nociceptive stimuli were localized bilaterally in two restricted clusters in the brain containing the primary and secondary somatosensory areas and the insular cortices consistent with the operculo-insular cortex. However, these activations completely disappeared when eliminating activations associated with the administration of olfactory stimuli, which were small but measurable. While the present experiments verify that the operculo-insular cortex plays a role in the processing of nociceptive input, they also show that it is not a pain-exclusive brain region and allow, in the experimental context, for the interpretation that the operculo-insular cortex splay a major role in the detection of and responding to salient events, whether or not these events are nociceptive or painful.

497 DIFFERENTIAL ROLE OF OPIOID RECEPTORS IN TIBIAL NERVE INHIBITION OF NOCICEPTIVE AND NON-NOCICEPTIVE BLADDER REFLEXES IN CATS

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology II1 Apr 2012497 DIFFERENTIAL ROLE OF OPIOID RECEPTORS IN TIBIAL NERVE INHIBITION OF NOCICEPTIVE AND NON-NOCICEPTIVE BLADDER REFLEXES IN CATS Abhijith Mally, Jeffrey Larson, P. Dafe Ogagan, Changfeng Tai, Bing Shen, Jicheng Wang, James Roppolo, and William C. de Groat Abhijith MallyAbhijith Mally Pittsburgh, PA More articles by this author , Jeffrey LarsonJeffrey Larson Pittsburgh, PA More articles by this author , P. Dafe OgaganP. Dafe Ogagan Pittsburgh, PA More articles by this author , Changfeng TaiChangfeng Tai Pittsburgh, PA More articles by this author , Bing ShenBing Shen Pittsburgh, PA More articles by this author , Jicheng WangJicheng Wang Pittsburgh, PA More articles by this author , James RoppoloJames Roppolo Pittsburgh, PA More articles by this author , and William C. de GroatWilliam C. de Groat Pittsburgh, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.567AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Electrical stimulation of somatic afferent pathways in the tibial nerve can inhibit bladder activity and therefore aid in the management of overactive bladder symptoms. Opioid peptides have a well known role in controlling pain mechanisms and are involved in somatic afferent inhibition of non-nociceptive bladder reflexes. We hypothesized that inhibition of irritation-induced bladder overactivity by tibial nerve stimulation could be due to activation of opioid receptors. We used naloxone to block the opioid receptors and assess the receptor function during tibial neuromodulation. METHODS Naloxone was administered to 20 cats in increasing cumulative doses. Saline (n=10) or .25% acetic acid (n=10) were utilized to irritate the bladder and induce overactivity. Bladder capacity and the degree of inhibition of bladder activity induced by tibial nerve stimulation were assessed by cystometrogram. RESULTS Infusion of acetic acid (AA) significantly reduced bladder capacity compared to saline. During CMG, tibial nerve stimulation (TNS) significantly inhibited bladder contraction and increased bladder capacity by 41.5±9.9% and 46.1±7.9% of the saline control capacity. Naloxone completely eliminated TNS inhibition of bladder overactivity. Naloxone did not change bladder capacity during AA irritation. However, during saline infusion, naloxone significantly reduced bladder capacity to 66.5±8.1% of the control capacity. During saline infusion TNS induced an acute increase in bladder capacity and an increase that persisted following stimulation. Naloxone administered during the post-stimulation inhibition still decreased bladder capacity. CONCLUSIONS These results indicate that opioid receptors have different roles in modulation of bladder reflexes induced by nociceptive and non-nociceptive stimuli and in somatic afferent inhibition of these reflexes, raising the possibility that opioid receptors may be a target for pharmacological treatment of lower urinary tract disorders. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e204 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Abhijith Mally Pittsburgh, PA More articles by this author Jeffrey Larson Pittsburgh, PA More articles by this author P. Dafe Ogagan Pittsburgh, PA More articles by this author Changfeng Tai Pittsburgh, PA More articles by this author Bing Shen Pittsburgh, PA More articles by this author Jicheng Wang Pittsburgh, PA More articles by this author James Roppolo Pittsburgh, PA More articles by this author William C. de Groat Pittsburgh, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Delayed postoperative latent pain sensitization revealed by the systemic administration of opioid antagonists in mice

The long-lasting post-surgical changes in nociceptive thresholds in mice, indicative of latent pain sensitization, were studied. The contribution of kappa opioid and N-methyl- d-aspartate (NMDA) receptors was assessed by the administration of nor-binaltorphimine or MK-801; dynorphin levels in the spinal cord were also determined. Animals underwent a plantar incision and/or a subcutaneous infusion of remifentanil (80 μg/kg), and mechanical thresholds (von Frey) were evaluated at different times. On day 21, after complete recovery of mechanical thresholds and healing of the wound, one of the following drugs was administered subcutaneously: (−)-naloxone (1 mg/kg), (+)-naloxone (1 mg/kg), naloxone-methiodide (3 mg/kg), or nor-binaltorphimine (5 mg/kg). Another group received subcutaneous MK-801 (0.15 mg/kg) before nor-binaltorphimine administration. Dynorphin on day 21 was determined in the spinal cord by immunoassay. In mice receiving remifentanil during surgery, the administration of (−)-naloxone or nor-binaltorphimine induced significant hyperalgesia even 5 months after manipulation. Nociceptive thresholds remained unaltered after (+)-naloxone or naloxone-methiodide. On day 21 after manipulation, the administration of MK-801 prevented nor-binaltorphimine-induced hyperalgesia. No changes in dynorphin levels were observed before or after opioid antagonist administration. In conclusion, surgery produced latent pain sensitization evidenced by opioid antagonist-precipitated hyperalgesia. The effect was stereospecific, centrally originated, and mediated by kappa opioid receptors. The blockade of nor-binaltorphimine-induced hyperalgesia by MK-801, suggests that NMDA receptors are also involved. Our results show for the first time that surgery induces latent, long-lasting changes in the processing of nociceptive information that can be induced by non-nociceptive stimuli such as the administration of opioid antagonists.

Anesthesia Literature Review

Anesthesia Literature Review

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes

Neuropathic pain is accompanied by both positive and negative sensory signs. To explore the spectrum of sensory abnormalities, 1236 patients with a clinical diagnosis of neuropathic pain were assessed by quantitative sensory testing (QST) following the protocol of DFNS (German Research Network on Neuropathic Pain), using both thermal and mechanical nociceptive as well as non-nociceptive stimuli. Data distributions showed a systematic shift to hyperalgesia for nociceptive, and to hypoesthesia for non-nociceptive parameters. Across all parameters, 92% of the patients presented at least one abnormality. Thermosensory or mechanical hypoesthesia (up to 41%) was more frequent than hypoalgesia (up to 18% for mechanical stimuli). Mechanical hyperalgesias occurred more often (blunt pressure: 36%, pinprick: 29%) than thermal hyperalgesias (cold: 19%, heat: 24%), dynamic mechanical allodynia (20%), paradoxical heat sensations (18%) or enhanced wind-up (13%). Hyperesthesia was less than 5%. Every single sensory abnormality occurred in each neurological syndrome, but with different frequencies: thermal and mechanical hyperalgesias were most frequent in complex regional pain syndrome and peripheral nerve injury, allodynia in postherpetic neuralgia. In postherpetic neuralgia and in central pain, subgroups showed either mechanical hyperalgesia or mechanical hypoalgesia. The most frequent combinations of gain and loss were mixed thermal/mechanical loss without hyperalgesia (central pain and polyneuropathy), mixed loss with mechanical hyperalgesia in peripheral neuropathies, mechanical hyperalgesia without any loss in trigeminal neuralgia. Thus, somatosensory profiles with different combinations of loss and gain are shared across the major neuropathic pain syndromes. The characterization of underlying mechanisms will be needed to make a mechanism-based classification feasible.

Basal opioid receptor binding is associated with differences in sensory perception in healthy human subjects: A [18F]diprenorphine PET study

The endogenous opioid system is involved in many body functions including pain processing and analgesia. To determine the role of basal opioid receptor availability in the brain in pain perception, twenty-three healthy subjects underwent positron emission tomography (PET) utilizing the subtype-nonselective opioid antagonist [18F]diprenorphine, quantitative sensory testing (QST) and the cold pressor test. Binding potentials (BPs) were calculated using a non-invasive reference tissue model and statistical parametric mapping was applied for t-statistical analysis on a voxelwise basis. We found that cold pain-sensitive subjects present a significantly lower BP in regions including the bilateral insular cortex and the left orbitofrontal cortex. In addition, correlation analysis revealed an inverse correlation between opioid BP in the bilateral motor and premotor region and perceptual wind-up. These findings indicate that interindividual differences in pain perception are partially accounted for by basal opioid receptor availability.A secondary aim of this study was to investigate the contribution of basal opioid receptor availability to the perception of non-nociceptive stimuli. The following negative correlations between regional opioid BP and scores of QST parameters were found: BP in the right premotor cortex and scores of alternating cold and warm stimuli, BP in the left midcingular cortex and scores of cold detection threshold, BP in the left insula and scores of mechanical detection threshold. These results suggest that the opioid receptor system is involved in the perception not only of pain but also of non-painful somatosensory stimuli.

Withdrawal reflexes in adductor muscles elicited by electrical and magnetic stimulation of the obturator nerve

The withdrawal reflex in the short head of the biceps femoris muscle after electrical stimulation of the sural nerve at the ankle has been investigated in numerous studies. These studies have described two distinct responses: early (R-II) and late (R-III). However, withdrawal reflex activity of the adductor muscles in the legs has not been studied systematically. Adductor muscle reflex activity is important because it can produce serious clinical problems, such as adductor spasticity and spasms, during bladder surgery. The present study examined withdrawal reflex features of adductor muscles obtained by electrical and magnetic stimulation of the obturator nerve (ON) in 34 normal healthy subjects. Early adductor muscle withdrawal reflex responses were elicited by ipsilateral ON electrical stimulation with a mean latency of 45.7+/-2.0 ms (responses in 94% of subjects). Reflex responses were also obtained using magnetic stimulation at a similar incidence rate. Contralateral ON electrical stimulation resulted in a similar reflex, but with a lower incidence. ON and femoral nerve electrical and magnetic coil stimulation produced similar low-incidence responses in the vastus medialis. These findings indicate that short latency adductor withdrawal reflexes are easily obtained on both sides following electrical or magnetic stimulation of the ON, and they can be elicited by both nociceptive and nonnociceptive stimuli. These reflexes prepare the body for a proper response to incoming signals and likely serve to protect the pelvic floor and pelvic organs.

Muscle Pain: Sensory Implications and Interaction With Motor Control

Muscle hyperalgesia and referred pain plays an important role in chronic musculoskeletal pain. New knowledge on the involved basic mechanisms and better methods to assess muscle pain in the clinic are needed to revise and optimize the treatment regimes. Increased muscle sensitivity is manifested as (1) pain evoked by a normally non-nociceptive stimulus (allodynia), (2) increased pain intensity evoked by nociceptive stimuli (hyperalgesia), or (3) increased referred pain areas with associated somatosensory changes. Quantitative sensory testing provides the possibility to evaluate these manifestations in a standardized way in patients suffering from musculoskeletal pain or in healthy volunteers. Some manifestations of sensitisation, such as expanded referred muscle pain areas in chronic musculoskeletal pain patients, can be explained from animal experiments showing extrasegmental spread of sensitisation. An important part of the pain manifestations (eg, tenderness and referred pain) related to chronic musculoskeletal disorders may be due to peripheral and central sensitization, which play a role in the transition from acute to chronic pain. In recent years, it has become evident that muscle pain can interfere with motor control strategies and different patters of interaction are seen during rest, static contractions, and dynamic conditions.

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.

The human μ-opioid receptor gene polymorphism 118A &gt; G decreases cortical activation in response to specific nociceptive stimulation.

The authors sought to investigate the role of a common single nucleotide polymorphism in the mu-opioid receptor gene (OPRM1) 118A > G for nociceptive sensory processing using event-related potentials (ERPs). Specific nociceptive (carbon dioxide [CO-sub-2]: 40% volume-to-volume [vol/vol] and 60% vol/vol) and nonnociceptive (hydrogen sulfide, 2 parts per million [ppm] and 4 ppm) stimuli were applied to the nasal mucosa of 45 volunteers. ERPs were recorded from a central lead. In this random sample, we found 37 noncarriers, 7 heterozygous carriers, and 1 homozygous carrier of the variant OPRM1 118G allele (allelic frequency, 10%). Amplitudes of nociceptive ERP in carriers of this allele were, on average, half as high as those of noncarriers. In discriminant analysis, ERP amplitude N1 response to the weaker nociceptive stimuli was the only ERP parameter that discriminated statistically significantly between carriers and noncarriers of the variant 118G allele. On the basis of N1-CO-sub-2 (40% vol/vol), the authors correctly backclassified 68.6% of the cases as carriers or noncarriers of the allele. The OPRM1 118A > G polymorphism specifically modulates nociceptive but not nonnociceptive cortical activation.

A Functional Role for Small-Conductance Calcium-Activated Potassium Channels in Sensory Pathways Including Nociceptive Processes

We investigated the role of small-conductance calcium-activated potassium (SK) and intermediate-conductance calcium-activated potassium channels in modulating sensory transmission from peripheral afferents into the rat spinal cord. Subunit-specific antibodies reveal high levels of SK3 immunoreactivity in laminas I, II, and III of the spinal cord. Among dorsal root ganglion neurons, both peripherin-positive (C-type) and peripherin-negative (A-type) cells show intense SK3 immunoreactivity. Furthermore, dorsal root-stimulated sensory responses recorded in vitro are inhibited when SK channel activity is increased with 1-ethyl-2-benzimidazolinone (1-EBIO). In vivo electrophysiological recordings show that neuronal responses to naturally evoked nociceptive and nonnociceptive stimuli increase after application of the selective SK channel blocker 8,14-diaza-1,7(1,4)-diquinolinacyclotetradecaphanedium di-trifluoroacetate (UCL 1848), indicating that SK channels are normally active in moderating afferent input. Conversely, neuronal responses evoked by mechanical stimuli are inhibited when SK channel activity is increased with 1-EBIO. These effects are reversed by the subsequent application of UCL 1848. Our data demonstrate that SK channels have an important role in controlling sensory input into the spinal cord.

Central sensitization in fibromyalgia and other musculoskeletal disorders.

Muscle hyperalgesia and referred pain play an important role in chronic musculoskeletal pain. New knowledge on the involved basic mechanisms and better methods to assess muscle pain in the clinic are needed to revise and optimize treatment regimens. Increased muscle sensitivity is manifested as pain evoked by a normally non-nociceptive stimulus (allodynia), increased pain intensity evoked by nociceptive stimuli (hyperalgesia), or increased referred pain areas with associated somatosensory changes. Some manifestations of sensitization, such as expanded referred muscle pain areas in patients with chronic musculoskeletal pain, can be explained from animal experiments showing extrasegmental spread of sensitization. An important part of the pain manifestations (eg, tenderness and referred pain) related to chronic musculoskeletal disorders may result from peripheral and central sensitization, which may play a role in the transition from acute to chronic pain.

Crf1-receptor antagonist cp-154526 reduces alerting-related cutaneous vasoconstriction in conscious rabbits

Cutaneous vasoconstrictor responses elicited by salient stimuli in conscious rabbits may be a sensitive physiological index of emotional arousal/anxiety. Ear-pinna blood flow was measured by preimplanted laser Doppler probes, and animals were exposed to situations involving different types of potentially salient stimuli before and after i.v. administration of CP-154526 (15 mg/kg) or diazepam (4 mg/kg). At rest, ear-pinna blood flow was stable (coefficient of varition=11 ±2) and remained at high level 93±13% of test time. Exposure to novel environment elicited flow fluctuations (coefficient of variation=79 ±8) and reduced amount of time spent at high level to 25 ±6%. Defined unconditioned stimuli caused rapid falls in ear-pinna flow, with nociceptive stimulation producing more vigorous and consistent effects (flow response index 0.66 ±0.02) compared with non-nociceptive (flow response index 0.49 ±0.04). CP-154526 slightly raised mean arterial pressure (from 81±2 to 93±3 mmHg), increased heart rate (from 198±1 to 220±4 beats/min) and produced a mild vasoconstriction in the ear-pinna bed (flow fell from 46±10 to 25±6 cm/s). CP-154526 substantially reduced cutaneous vasoconstrictor responses elicited by the exposure to novel environment and by defined non-nociceptive stimuli, with flow-response index fall from 0.53±0.10 to 0.17±0.09 and from 0.47±0.04 to 0.24±0.04, respectively, without affecting responses to nociceptive stimuli. Diazepam reduced only vasoconstrictor responses elicited by the exposure to novel environment, with flow-response index fall from 0.40±0.12 to 0.27±0.07. Sensitivity of rapid changes in rabbit ear-pinna blood flow to anxiolytic drugs supports the idea that increased cutaneous vascular tone reflects enhanced arousal in rabbits.