Nociceptive Specific Research Articles

Anodal transcutaneous spinal direct current stimulation influences the amplitude of pain-related evoked potentials in healthy subjects

It has already been described that transcutaneous spinal direct current stimulation (tsDCS) can selectively influence nociceptive evoked potentials. This study is the first aiming to prove an influence of tsDCS on pain-related evoked potentials (PREP) using concentric surface electrodes (CE), whose nociceptive specificity is still under discussion. 28 healthy subjects participated in this sham-controlled, double-blind cross-over study. All subjects underwent one session of anodal and one session of sham low-thoracic tsDCS. Before and after the intervention, PREP using CE, PREP-induced pain perception and somatosensory evoked potentials (SEP) were assessed on the right upper and lower limb. We found a decrease in PREP amplitude at the lower limb after sham stimulation, but not after anodal tsDCS, while SEP remained unchanged under all studied conditions. There was no difference between the effects of anodal tsDCS and sham stimulation on the studied parameters assessed at the upper limb. PREP-induced pain of the upper and lower limb increased after anodal tsDCS. The ability of influencing PREP using a CE at the spinal level in contrast to SEP suggests that PREP using CE follows the spinothalamic pathway and supports the assumption that it is specifically nociceptive. However, while mainly inhibitory effects on nociceptive stimuli have already been described, our results rather suggest that anodal tsDCS has a sensitizing effect. This may indicate that the mechanisms underlying the elicitation of PREP with CE are not the same as for the other nociceptive evoked potentials. The effects on the processing of different types of painful stimuli should be directly compared in future studies.

Network Model of Nociceptive Processing in the Superficial Spinal Dorsal Horn Reveals Mechanisms of Hyperalgesia, Allodynia, and Spinal Cord Stimulation.

The spinal dorsal horn (DH) processes sensory information and plays a key role in transmitting nociception to supraspinal centers. Loss of DH inhibition during neuropathic pain unmasks a pathway from non-nociceptive Aβ-afferent inputs to superficial dorsal horn (SDH) nociceptive-specific (NS) projection neurons, and this change may contribute to hyperalgesia and allodynia. We developed and validated a computational model of SDH neuronal circuitry that linked non-nociceptive Aβ-afferent inputs in lamina II/III to a NS projection neuron in lamina I via a network of excitatory interneurons. The excitatory pathway and the NS projection neuron were in turn gated by inhibitory interneurons with connections based on prior patch clamp recordings. Changing synaptic weights in the computational model to replicate neuropathic pain states unmasked a low-threshold excitatory pathway to NS neurons similar to experimental recordings. Spinal cord stimulation (SCS) is an effective therapy for neuropathic pain, and accumulating experimental evidence indicates that NS neurons in the SDH also respond to SCS. Accounting for these responses may inform therapeutic improvements, and we quantified responses to SCS in the SDH network model and examined the role of different modes of inhibitory control in modulating NS neuron responses to SCS. We combined the SDH network model with a previously published model of the deep dorsal horn (DDH) and identified optimal stimulation frequencies across different neuropathic pain conditions. Finally, we found that SCS-generated inhibition did not completely suppress model NS activity during simulated pinch inputs, providing an explanation of why SCS does not eliminate acute pain.

Insular cortical descending projections facilitate neuronal responses to noxious but not innoxious stimulation in rat trigeminal spinal subnucleus caudalis

The insular cortex (IC) receives orofacial nociceptive information. Pyramidal neurons in IC layer V send their axons to various brain regions, such as the trigeminal spinal subnucleus caudalis (Sp5C), parabrachial nucleus, and periaqueductal gray. However, little information has been available about the functions of these descending projections from the IC. This study aimed to elucidate the effect of IC → Sp5C on neuronal spike firings responding to noxious and innoxious stimuli to the face of the rat receiving an injection of adeno-associated virus encoding modified channelrhodopsin-2 (ChR2) fused to mCherry under the control of the human synapsin promotor. We classified Sp5C neurons responding to mechanical stimuli into three groups: low-threshold (LT), nociceptive specific (NS), and wide dynamic range (WDR) neurons, which respond to innoxious stimuli (brushing) only, noxious mechanical stimuli (pinching) only, and both noxious and innoxious stimuli, respectively. Neuronal activities of IC neurons were activated by photostimulation (repetitive pulses at 20 Hz for 5 Hz) to the IC that consistently induced action potentials in IC layer V pyramidal neurons. LT neurons showed comparable spike firing rates to brushing the facial skin before and during ChR2 activation induced by photostimulation. In contrast, NS neurons showed an increase in their firing frequency to pinching during ChR2 activation. On the other hand, WDR neurons increased their Sp5C neuronal firing to pinching during ChR2 activation without changing their firing rates to innoxious mechanical stimuli. These results suggest that the IC descending projections facilitate nociception by increasing Sp5C neuronal activities responding to noxious mechanical stimuli.

WE-220. Nociceptive specificity with intra-epidermal electrical stimulation?

WE-220. Nociceptive specificity with intra-epidermal electrical stimulation?

Effects of Early Life Stress or Inflammation on Spinal Dorsal Horn Neuronal Responses to Perineal Mechanical Stimulation in Male Mice

This study characterized responses of dorsal horn neurons to perineal mechanical stimulation in adult male C57Bl/6J mice after neonatal maternal separation (NMS) or neonatal pelvic inflammation (NPI). For NMS, pups were removed from their home cage 4 hrs daily on P1-P21; controls were left undisturbed. For NPI, pups were anesthetized on P12 and Zymosan A (10 mg/ml, 20 ul) was injected into the pelvic floor musculature (Zymo); controls were exposed to anesthesia (Anes). At 12-15 weeks of age, mice were anesthetized and prepared for in vivo spinal recordings. Single-unit extracellular recordings were discriminated from background, converted into uniform pulses, and saved to computer as peristimulus-time histograms. Von Frey filaments (15-180 g) were applied to the perineum and evoked activity was calculated as total activity during 10-sec stimulus minus spontaneous activity in 10-sec prior to stimulus. Responses to non-noxious input and to a heterotopic noxious conditioning stimulus (HCNS) were determined for each neuron (Type I inhibited >20%, all others Type II). A total of 23 control and 17 NMS neurons were recorded. Chi-square showed no difference in the proportions of wide dynamic range (WDR) and nociceptive specific (NS) neurons between groups. Linear regression showed no difference in the slopes for WDR or NS neurons between groups. The proportion of Type I neurons was significantly reduced by NMS (Chi-square, p<0.05). A total of 9 Anes and 17 Zymo neurons were recorded. Chi-square showed no difference in the proportions of WDR and NS neurons, but the slopes for WDR (p<0.05) and NS (p<0.01) neurons were different between groups. NPI did not change the proportions of Type I neurons (Chi-square, NS). Early life stress and inflammation differentially affect subpopulations of dorsal horn neurons responsive to UBD. Changes in gain and the effect of HNCS reflect alterations in spinal transmission consistent with development of hypersensitivity.

Optogenetic Modulation of Primary Afferent Neurons in Vivo Produces Mixed Effects in Spinal Neuronal Responses During Urinary Bladder Distention

This ongoing study characterizes the responses of dorsal horn neurons to graded urinary bladder distention (UBD) during optogenetic modulation of bladder-innervating primary afferent neurons. Ai32 and Ai39 mice were crossed with Scn10atm3(cre/ERT2)Jwo mice to generate offspring expressing ChR2(H134R)/EYFP or NpHR3.0/EYFP, respectively, in Nav1.8+ primary afferents. At 6-8 weeks of age, female heterozygous mice were anesthetized and instrumented with a transurethral catheter. A fiber optic was passed through the catheter and coupled to a diode-pumped solid-state laser for photomodulation. Mice were prepared for in vivo spinal recordings. Single-unit extracellular recordings were discriminated from background, converted into uniform pulses, and saved to computer as peristimulus-time histograms. UBD (20, 40, and 60 mmHg) was administered without and with concurrent photomodulation. Evoked activity was calculated as total activity during 10-sec UBD minus spontaneous activity in 10-sec period prior to UBD. Responses to cutaneous non-noxious mechanical input were used to determine whether neurons were wide dynamic range (WDR) or nociceptive specific (NS). Preliminary data from Scn10aCre;Ai39 mice demonstrate that 2/9 spinal neurons were uniformly inhibited by afferent photoinhibition (589 nm) during UBD and 7/9 exhibited mixed responses (facilitation at 20 mmHg, inhibition at 40 and 60 mmHg). 8/9 of these neurons were WDR and 1/9 was NS. Preliminary data from Scn10aCre;Ai32 mice show that 1/4 UBD-responsive spinal neurons was uniformly inhibited, 1/4 was uniformly excited, and 2/4 exhibited mixed responses to afferent photoexcitation (473 nm) during UBD. 2/2 neurons were WDR and 2/2 were NS. Application of a heterotopic noxious conditioning stimulus (HCNS) during 60 mmHg UBD revealed no effect on neurons with a mixed phenotype, but HCNS produced >20% inhibition of neurons that were uniformly excited or inhibited during photoexcitation. In sum, these results reflect the complexity of viscerosensory spinal neuronal processing through excitation, inhibition, and disinhibition of second order neurons via multiple mechanisms. Grant support from K01DK101681.

Delta-9-tetrahydrocannabinol reduces the performance in sensory delayed discrimination tasks. A pharmacological-fMRI study in healthy volunteers

BackgroundCannabis proofed to be effective in pain relief, but one major side effect is its influence on memory in humans. Therefore, the role of memory on central processing of nociceptive information was investigated in healthy volunteers. MethodsIn a placebo-controlled cross-over study including 22healthy subjects, the effect of 20mg oral Δ9-tetrahydrocannabinol (THC) on memory involving nociceptive sensations was studied, using a delayed stimulus discrimination task (DSDT). To control for nociceptive specificity, a similar DSDT-based study was performed in a subgroup of thirteen subjects, using visual stimuli. ResultsFor each nociceptive stimulus pair, the second stimulus was associated with stronger and more extended brain activations than the first stimulus. These differences disappeared after THC administration. The THC effects were mainly located in two clusters comprising the insula and inferior frontal cortex in the right hemisphere, and the caudate nucleus and putamen bilaterally. These cerebral effects were accompanied in the DSDT by a significant reduction of correct ratings from 41.61% to 37.05% after THC administration (rm-ANOVA interaction “drug” by “measurement”: F (1,21)=4.685, p=0.042). Rating performance was also reduced for the visual DSDT (69.87% to 54.35%; rm-ANOVA interaction of “drug” by “measurement”: F (1,12)=13.478, p=0.003) and reflected in a reduction of stimulus-related brain deactivations in the bilateral angular gyrus. ConclusionsResults suggest that part of the effect of THC on pain may be related to memory effects. THC reduced the performance in DSDT of nociceptive and visual stimuli, which was accompanied by significant effects on brain activations. However, a pain specificity of these effects cannot be deduced from the data presented.

Decanoic acid attenuates the excitability of nociceptive trigeminal primary and secondary neurons associated with hypoalgesia.

BackgroundAcute application of decanoic acid (DA) in vivo suppresses the excitability of spinal trigeminal nucleus caudalis (SpVc) wide dynamic range (WDR) neurons associated with the short-term mechanical hypoalgesia via muscarinic M2 receptor signaling; however, the effect of DA on nociceptive trigeminal ganglion (TG) and SpVc nociceptive-specific (NS) neuronal excitability under in vivo conditions remains to be determined. The present study investigated whether this effect could be observed in naive rats.ResultsExtracellular single-unit recordings were made from TG and SpVc NS neurons of pentobarbital-anesthetized rats in response to orofacial noxious mechanical stimuli. DA inhibited the mean firing frequency of both TG and SpVc NS neurons, reaching a maximum inhibition of discharge frequency within 1–5 minutes and reversing after approximately 10-minutes; however, this DA-induced suppression of SpVc NS neuronal firing frequency did not occur in rats administered with methoctramine intravenously prior to stimulation.ConclusionThis in vivo study indicated that firing of TG and SpVc NS neurons induced by mechanical hypoalgesia through peripheral M2 receptors could be inhibited by acutely administered DA, implicating the potential of DA in the future treatment of trigeminal pain.PerspectiveThis article presents that the acute DA application suppresses the excitability of TG and SpVc NS neurons associated with mechanical hypoalgesia via peripheral M2 receptor signaling, supporting DA as a potential therapeutic agent in complementary and alternative medicine for the attenuation of nociception.

Characterization and pharmacological modulation of noci-responsive deep dorsal horn neurons across diverse rat models of pathological pain.

This overview compares the activity of wide dynamic range (WDR) and nociceptive specific (NS) neurons located in the deep dorsal horn across different rat models of pathological pain and following modulation by diverse pharmacology. The data were collected by our group under the same experimental conditions over numerous studies to facilitate comparison. Spontaneous firing of WDR neurons was significantly elevated (>3.7 Hz) in models of neuropathic, inflammation, and osteoarthritic pain compared with naive animals (1.9 Hz) but was very low (<0.5 Hz) and remained unchanged in NS neurons. WDR responses to low-intensity mechanical stimulation were elevated in neuropathic and inflammation models. WDR responses to high-intensity stimuli were enhanced in inflammatory (heat) and osteoarthritis (mechanical) models. NS responses to high-intensity stimulation did not change relative to control in any model examined. Several therapeutic agents reduced both evoked and spontaneous firing of WDR neurons (e.g., TRPV1, TRPV3, Nav1.7, Nav1.8, P2X7, P2X3, H3), other targets affected neither evoked nor spontaneous firing of WDR neurons (e.g., H4, TRPM8, KCNQ2/3), and some only modulated evoked (e.g, ASIC1a, Cav3.2) whereas others decreased evoked but affected spontaneous activity only in specific models (e.g., TRPA1, CB2). Spontaneous firing of WDR neurons was not altered by any peripherally restricted compound or by direct administration of compounds to peripheral sites, although the same compounds decreased evoked activity. Compounds acting centrally were effective against this endpoint. The diversity of incoming/modulating inputs to the deep dorsal horn positions this group of neurons as an important intersection within the pain system to validate novel therapeutics. NEW & NOTEWORTHY Data from multiple individual experiments were combined to show firing properties of wide dynamic range and nociceptive specific spinal dorsal horn neurons across varied pathological pain models. This high-powered analysis describes the sensitization following different forms of injury. Effects of diverse pharmacology on these neurons is also summarized from published and unpublished data all recorded under the same conditions to facilitate comparison. This comprehensive overview describes the function and utility of these neurons.

The medullary dorsal reticular nucleus as a relay for descending pronociception induced by the mGluR5 in the rat infralimbic cortex

Metabotropic glutamate receptor 5 (mGluR5) activation in the infralimbic cortex (IL) induces pronociceptive behavior in healthy and monoarthritic rats. Here we studied whether the medullary dorsal reticular nucleus (DRt) and the spinal TRPV1 are mediating the IL/mGluR5-induced spinal pronociception and whether the facilitation of pain behavior is correlated with changes in spinal dorsal horn neuron activity. For drug administrations, all animals had a cannula in the IL as well as a cannula in the DRt or an intrathecal catheter. Heat-evoked paw withdrawal was used to assess pain behavior in awake animals. Spontaneous and heat-evoked discharge rates of single DRt neurons or spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons were evaluated in lightly anesthetized animals.Activation of the IL/mGluR5 facilitated nociceptive behavior in both healthy and monoarthritic animals, and this effect was blocked by lidocaine or GABA receptor agonists in the DRt. IL/mGluR5 activation increased spontaneous and heat–evoked DRt discharge rates in healthy but not monoarthritic rats. In the spinal dorsal horn, IL/mGluR5 activation increased spontaneous activity of WDR neurons in healthy animals only, whereas heat-evoked responses of WDR and NS neurons were increased in both experimental groups. Intrathecally administered TRPV1 antagonist prevented the IL/mGluR5-induced pronociception in both healthy and monoarthritic rats.The results suggest that the DRt is involved in relaying the IL/mGluR5-induced spinal pronociception in healthy control but not monoarthritic animals. Spinally, the IL/mGluR5-induced behavioral heat hyperalgesia is mediated by TRPV1 and associated with facilitated heat-evoked responses of WDR and NS neurons.

Neuronal hyperexcitability in the ventral posterior thalamus of neuropathic rats: modality selective effects of pregabalin.

Neuropathic pain represents a substantial clinical challenge; understanding the underlying neural mechanisms and back-translation of therapeutics could aid targeting of treatments more effectively. The ventral posterior thalamus (VP) is the major termination site for the spinothalamic tract and relays nociceptive activity to the somatosensory cortex; however, under neuropathic conditions, it is unclear how hyperexcitability of spinal neurons converges onto thalamic relays. This study aimed to identify neural substrates of hypersensitivity and the influence of pregabalin on central processing. In vivo electrophysiology was performed to record from VP wide dynamic range (WDR) and nociceptive-specific (NS) neurons in anesthetized spinal nerve-ligated (SNL), sham-operated, and naive rats. In neuropathic rats, WDR neurons had elevated evoked responses to low- and high-intensity punctate mechanical stimuli, dynamic brushing, and innocuous and noxious cooling, but less so to heat stimulation, of the receptive field. NS neurons in SNL rats also displayed increased responses to noxious punctate mechanical stimulation, dynamic brushing, noxious cooling, and noxious heat. Additionally, WDR, but not NS, neurons in SNL rats exhibited substantially higher rates of spontaneous firing, which may correlate with ongoing pain. The ratio of WDR-to-NS neurons was comparable between SNL and naive/sham groups, suggesting relatively few NS neurons gain sensitivity to low-intensity stimuli leading to a "WDR phenotype." After neuropathy was induced, the proportion of cold-sensitive WDR and NS neurons increased, supporting the suggestion that changes in frequency-dependent firing and population coding underlie cold hypersensitivity. In SNL rats, pregabalin inhibited mechanical and heat responses but not cold-evoked or elevated spontaneous activity.

D-aspartate modulates nociceptive-specific neuron activity and pain threshold in inflammatory and neuropathic pain condition in mice.

D-Aspartate (D-Asp) is a free D-amino acid found in the mammalian brain with a temporal-dependent concentration based on the postnatal expression of its metabolizing enzyme D-aspartate oxidase (DDO). D-Asp acts as an agonist on NMDA receptors (NMDARs). Accordingly, high levels of D-Asp in knockout mice for Ddo gene (Ddo −/−) or in mice treated with D-Asp increase NMDAR-dependent processes. We have here evaluated in Ddo −/− mice the effect of high levels of free D-Asp on the long-term plastic changes along the nociceptive pathway occurring in chronic and acute pain condition. We found that Ddo −/− mice show an increased evoked activity of the nociceptive specific (NS) neurons of the dorsal horn of the spinal cord (L4–L6) and a significant decrease of mechanical and thermal thresholds, as compared to control mice. Moreover, Ddo gene deletion exacerbated the nocifensive responses in the formalin test and slightly reduced pain thresholds in neuropathic mice up to 7 days after chronic constriction injury. These findings suggest that the NMDAR agonist, D-Asp, may play a role in the regulation of NS neuron electrophysiological activity and behavioral responses in physiological and pathological pain conditions.

PC1, a non-peptide PKR1-preferring antagonist, reduces pain behavior and spinal neuronal sensitization in neuropathic mice

Peripheral neuropathy is characterized by abnormal pain responses triggered by the release of several mediators and neuronal hyperexcitability at the spinal cord level. Emerging evidence indicates that the enhanced activity of dorsal horn neurons requires communication with glia and microglia, cells that are physiologically involved in neuronal wellbeing. Prokineticins (PKs), which include PK1 and PK2, represent a novel family of chemokines characterized by a unique structural motif comprising five disulfide bonds. They are expressed in the peripheral and central nervous system. PKs bind two G protein coupled receptors, PKR1 and PKR2, and participate in the regulation of several biological processes, including pain sensation. This study aimed to investigate the anti-nociceptive effect of PC1, a non-peptide PKR1-preferring antagonist, in a mouse model of neuropathic pain. To do this, we assessed the activity of spinal cord nociceptive neurons as well as astrocyte and microglia phenotypes after repeated administration of PC1 in vivo. PC1 treatment strongly delayed the development of thermal hyperalgesia and tactile and mechanical allodynia. It also reduced spinal microglial and glial activation 8 days post injury in spared nerve injury (SNI) mice. Neuropathic mice showed an increased level of PK2 protein in the spinal cord, mostly in astrocytes. PC1 treatment completely reversed the increased responsiveness to mechanical stimuli, the decreased threshold of neuronal activation, and the increased spontaneous activity that were observed in nociceptive specific (NS) neurons of SNI mice.

The somatostatin receptor 4 agonist J-2156 reduces mechanosensitivity of peripheral nerve afferents and spinal neurons in an inflammatory pain model

Somatostatin (SST) is a peptide hormone that regulates the endocrine system and affects neurotransmission via interaction with G protein-coupled SST receptors and inhibition of the release of different hormones. The aim of this study was to investigate whether the analgesic properties of the selective SSTR4 agonist J-2156 are mediated via peripheral and/or spinal receptors.Effect on mechanical hyperalgesia in the Complete Freund׳s Adjuvant (CFA) model was measured after intraperitoneal application of J-2156. Electrophysiological neuronal recordings were conducted 24h after injection of CFA or vehicle into the paw of Wistar rats. Mechanosensitivity of peripheral afferents of the saphenous nerve as well as of spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were measured after systemic or spinal application of J-2156.In CFA animals J-2156 dose dependently reduced hyperalgesia in behavioral studies. The minimal effective dose was 0.1mg/kg. Mechanosensitivity of peripheral afferents and spinal neurons was significantly reduced by J-2156. NS neurons were dose dependently inhibited by J-2156 while in WDR neurons only the highest concentration of 100µM had an effect. In sham controls, J-2156 had no effect on neuronal activity.We demonstrated that J-2156 dose-dependently reduces peripheral and spinal neuronal excitability in the CFA rat model without affecting physiological pain transmission. Given the high concentration of the compound required to inhibit spinal neurons, it is unlikely that the behavioral effect seen in CFA model is mediated centrally. Overall these data demonstrated that the analgesic effect of J-2156 is mediated mainly via peripheral SST4 receptors.

Effect of Spinal Manipulation Thrust Duration on Trunk Mechanical Activation Thresholds of Nociceptive-Specific Lateral Thalamic Neurons

ObjectiveThe objective of this preliminary study was to determine if high-velocity, low-amplitude spinal manipulation (HVLA-SM) thrust duration alters mechanical trunk activation thresholds of nociceptive-specific (NS) lateral thalamic neurons. MethodsExtracellular recordings were obtained from 18 NS neurons located in 2 lateral thalamic nuclei (ventrolateral [n = 12] and posterior [n = 6]) in normal anesthetized Wistar rats. Response thresholds to electronic von Frey anesthesiometer (rigid tip) mechanical trunk stimuli applied in 3 lumbar directions (dorsal-ventral, 45° caudal, and 45° cranial) were determined before and immediately after the delivery of 3 HVLA-SM thrust durations (time control 0, 100, and 400 milliseconds). Mean changes in mechanical trunk activation thresholds were compared using a mixed model analysis of variance. ResultsHigh-velocity, low-amplitude spinal manipulation duration did not significantly alter NS lateral thalamic neurons' mechanical trunk responses to any of the 3 directions tested with the anesthesiometer. ConclusionsThis study is the first to examine the effect of HVLA-SM thrust duration on NS lateral thalamic mechanical response thresholds. High-velocity, low-amplitude spinal manipulation thrust duration did not affect mechanical trunk thresholds.

The bradykinin B1 receptor antagonist BI113823 reverses inflammatory hyperalgesia by desensitization of peripheral and spinal neurons.

Bradykinin is a neuropeptide released after tissue damage which plays an important role in inflammatory pain. The up-regulation of the bradykinin B1 receptor in response to inflammation makes it an attractive target for drug development. Aim was to investigate if the selective B1 receptor antagonist BI113823 reduces inflammation-induced mechanical hyperalgesia and if the effect is mediated via peripheral and/or spinal B1 receptor antagonism. Electrophysiological recordings of peripheral afferents and spinal neurons were combined with behavioural experiments to better understand the underlying mechanisms of B1 receptor antagonism. Experiments were performed 24 h after injection of complete Freund's adjuvant (CFA) or saline into the paw of Wistar rats. A gene expression analysis for the B1 receptor was performed in different tissues. BI113823 was administered orally or intrathecally to assess effects on CFA-induced hyperalgesia. Peripheral afferents of the saphenous nerve as well as spinal wide dynamic range (WDR) and nociceptive-specific (NS) neurons were recorded, and mechanosensitivity was measured before and after BI113823 administration. BI113823 reduced CFA-induced mechanical hyperalgesia when administered orally or intrathecally. An increased B1 receptor gene expression was found in peripheral and spinal neural tissue. BI113823 significantly reduced mechanosensitivity of peripheral afferents and spinal NS neurons, but had no effect on WDR neurons. The selective bradykinin B1 receptor antagonist BI113823 reduces CFA-induced mechanical hyperalgesia which is mediated via antagonism of peripheral as well as spinal bradykinin B1 receptors. The selective modulation of CFA-sensitized spinal NS neurons by BI113823 could be a promising property for the treatment of inflammatory pain.

Effect of Spinal Manipulation Thrust Magnitude on Trunk Mechanical Activation Thresholds of Lateral Thalamic Neurons

ObjectivesHigh-velocity low-amplitude spinal manipulation (HVLA-SM), as performed by doctors who use manual therapy (eg, doctors of chiropractic and osteopathy), results in mechanical hypoalgesia in clinical settings. This hypoalgesic effect has previously been attributed to alterations in peripheral and/or central pain processing. The objective of this study was to determine whether thrust magnitude of a simulated HVLA-SM alters mechanical trunk response thresholds in wide dynamic range (WDR) and/or nociceptive specific (NS) lateral thalamic neurons. MethodsExtracellular recordings were carried out in the thalamus of 15 anesthetized Wistar rats. Lateral thalamic neurons having receptive fields, which included the lumbar dorsal-lateral trunk, were characterized as either WDR (n=22) or NS (n=25). Response thresholds to electronic von Frey (rigid tip) mechanical trunk stimuli were determined in 3 directions (dorsal-ventral, 45° caudalward, and 45° cranialward) before and immediately after the dorsal-ventral delivery of a 100-millisecond HVLA-SM at 3 thrust magnitudes (control, 55%, 85% body weight). ResultsThere was a significant difference in mechanical threshold between 85% body weight manipulation and control thrust magnitudes in the dorsal-ventral direction in NS neurons (P=.01). No changes were found in WDR neurons at either HVLA-SM thrust magnitude. ConclusionsThis study is the first to investigate the effect of HVLA-SM thrust magnitude on WDR and NS lateral thalamic mechanical response threshold. Our data suggest that, at the single lateral thalamic neuron level, there may be a minimal spinal manipulative thrust magnitude required to elicit an increase in trunk mechanical response thresholds.

Postnatal Temporal, Spatial and Modality Tuning of Nociceptive Cutaneous Flexion Reflexes in Human Infants

Cutaneous flexion reflexes are amongst the first behavioural responses to develop and are essential for the protection and survival of the newborn organism. Despite this, there has been no detailed, quantitative study of their maturation in human neonates. Here we use surface electromyographic (EMG) recording of biceps femoris activity in preterm (<37 weeks gestation, GA) and term (≥37 weeks GA) human infants, less than 14 days old, in response to tactile, punctate and clinically required skin-breaking lance stimulation of the heel. We show that all infants display a robust and long duration flexion reflex (>4 seconds) to a single noxious skin lance which decreases significantly with gestational age. This reflex is not restricted to the stimulated limb: heel lance evokes equal ipsilateral and contralateral reflexes in preterm and term infants. We further show that infant flexion withdrawal reflexes are not always nociceptive specific: in 29% of preterm infants, tactile stimulation evokes EMG activity that is indistinguishable from noxious stimulation. In 40% of term infants, tactile responses are also present but significantly smaller than nociceptive reflexes. Infant flexion reflexes are also evoked by application of calibrated punctate von Frey hairs (vFh), 0.8–17.2 g, to the heel. Von Frey hair thresholds increase significantly with gestational age and the magnitude of vFh evoked reflexes are significantly greater in preterm than term infants. Furthermore flexion reflexes in both groups are sensitized by repeated vFh stimulation. Thus human infant flexion reflexes differ in temporal, modality and spatial characteristics from those in adults. Reflex magnitude and tactile sensitivity decreases and nociceptive specificity and spatial organisation increases with gestational age. Strong, relatively non-specific, reflex sensitivity in early life may be important for driving postnatal activity dependent maturation of targeted spinal cord sensory circuits.

The role of the dopamine D2 receptor in descending control of pain induced by motor cortex stimulation in the neuropathic rat

We studied in rats with a spinal nerve ligation-induced neuropathy whether dopamine D2 receptors (D2Rs) play a role in descending control of pain induced by stimulation of the primary motor cortex (M1). Noxious heat-evoked responses were determined in spinal dorsal horn wide-dynamic range (WDR) and nociceptive-specific (NS) neurons, with and without electrical M1 stimulation. A D2R antagonist, raclopride, was administered into the dorsal striatum or spinally in attempts to reverse spinal antinociception induced by M1 stimulation. Moreover, influence of M1 stimulation on the noxious heat-induced limb withdrawal reflex was determined following block of spinal D2Rs with raclopride or a lidocaine-induced block of the hypothalamic A11 cell group, the main source of spinal dopamine. Striatal administration of raclopride enhanced the heat-evoked baseline responses of WDR but not NS neurons and reversed the M1 stimulation-induced suppression of the heat response in WDR neurons. Following spinal administration of raclopride, M1 stimulation failed to suppress the heat response of WDR neurons, whereas the heat response of NS neurons was enhanced by M1-stimulation. After blocking the A11 with lidocaine or spinal D2Rs with raclopride, M1 stimulation failed to suppress the noxious heat-evoked withdrawal reflex. The results indicate that descending pain control induced by stimulation of the M1 cortex in neuropathic animals involves supraspinal (presumably striatal) and, through A11, spinal D2Rs. Supraspinal and spinal D2Rs have partly dissociative effects on spinal dorsal horn WDR and NS neurons, possibly reflecting differential roles and wirings that these sensory neurons have in pain-processing circuitries.

Do we activate specifically somatosensory thin fibres with the concentric planar electrode? A scalp and intracranial EEG study

Laser-evoked potentials (LEPs) are acknowledged as the most reliable laboratory tool for assessing thermal and pain pathways. Electrical stimulation with a newly developed planar concentric electrode, delivering stimuli limited to the superficial skin layers, has been suggested to provide selective activation of Aδ fibres without the inconveniences linked to laser stimulation. The aim of our study was to compare the scalp and intracranial responses to planar concentric electrode stimulation (CE-SEPs) with those of LEPs and standard somatosensory-evoked potentials (SEPs). Sixteen healthy subjects, 6 patients with intracortical electrodes, and 2 patients with selective lesions of the spinothalamic pathway were submitted to Neodymium:Yttrium-Aluminium-Perovskite laser stimulations, and electrical stimulations using standard electrodes or planar concentric electrodes (CE). In both healthy controls and epileptic implanted patients, CE- and standard SEPs showed significantly shorter latencies than LEPs. This is consistent with Aβ-fibre activation, peripheral activation time being unable to account for longer LEP latencies. In the patients with spinothalamic lesions, LEPs were absent after stimulation of the affected territory, while CE-SEPs were still present. For these 2 reasons, we conclude that the planar CE does not selectively activate the Aδ and C fibers, but coexcites a significant proportion of large myelinated Aβ fibres that dominate the ensuing cortical response. The use of CE-SEPs for the detection of spinothalamic system lesions is therefore not warranted; the planar electrode can, however, represent a useful tool to study nociceptive reflexes, which can be reliably elicited even in the presence of Aβ coactivation.