Noxious Heat Stimuli Research Articles

In vivo optogenetic activation of Nav1.8+ cutaneous nociceptors and their responses to natural stimuli.

Optogenetic methods that utilize expression of the light-sensitive protein channelrhodopsin-2 (ChR2) in neurons have enabled selective activation of specific subtypes or groups of neurons to determine their functions. Using a transgenic mouse model in which neurons natively expressing Nav1.8 (a tetrodotoxin-resistant voltage-gated sodium channel) also express the light-gated channel ChR2, we have been able to determine the functional properties of Nav1.8-expressing cutaneous nociceptors of the glabrous skin in vivo. Most (44 of 53) of the C-fiber nociceptors isolated from Nav1.8-ChR2+ mice were found to be responsive to blue (470 nm) light. Response characteristics, including conduction velocity and responses to mechanical stimuli, were comparable between nociceptors isolated from Nav1.8-ChR2+ and control mice. Interestingly, while none of the non-light-responsive C-fibers were sensitive to heat or cold, nearly all (77%) light-sensitive fibers were excited by mechanical and thermal stimuli, suggesting that Nav1.8 is predominantly expressed by C-fiber nociceptors that are responsive to multiple stimulus modalities. The ability to activate peripheral nociceptors with light provides a method of stimulation that is noninvasive, does not require mechanical interruption of the skin, and accesses receptive fields that might be difficult or impossible to stimulate with standard stimuli while allowing repeated stimulation without injuring the skin.NEW & NOTEWORTHY Transgenic mice that express the blue light-sensitive protein channelrhodopsin2 (ChR2) in nociceptive nerve fibers that contain voltage-gated sodium channel Nav1.8 were used to determine functional properties of these afferent fibers. Electrophysiological recordings in vivo revealed that most nociceptive fibers that possess Nav1.8 are C-fiber nociceptors that respond to multiple stimulus modalities. Furthermore, responses evoked by blue light stimulation were comparable to those elicited by noxious mechanical, heat, and cold stimuli.

FGF13 Selectively Regulates Heat Nociception by Interacting with Nav1.7

The current knowledge about heat nociception is mainly confined to the thermosensors, including the transient receptor potential cation channel V1 expressed in the nociceptive neurons of dorsal root ganglion (DRG). However, the loss of thermosensors only partially impairs heat nociception, suggesting the existence of undiscovered mechanisms. We found that the loss of an intracellular fibroblast growth factor (FGF), FGF13, in the mouse DRG neurons selectively abolished heat nociception. The noxious heat stimuli could not evoke the sustained action potential firing in FGF13-deficient DRG neurons. Furthermore, FGF13 interacted with the sodium channel Nav1.7 in a heat-facilitated manner. FGF13 increased Nav1.7 sodium currents and maintained the membrane localization of Nav1.7 during noxious heat stimulation, enabling the sustained firing of action potentials. Disrupting the FGF13/Nav1.7 interaction reduced the heat-evoked action potential firing and nociceptive behavior. Thus, beyond the thermosensors, the FGF13/Nav1.7 complex is essential for sustaining the transmission of noxious heat signals.

Thermal grill conditioning: Effect on contact heat evoked potentials

The ‘thermal grill illusion’ (TGI) is a unique cutaneous sensation of unpleasantness, induced through the application of interlacing warm and cool stimuli. While previous studies have investigated optimal parameters and subject characteristics to evoke the illusion, our aim was to examine the modulating effect as a conditioning stimulus. A total of 28 healthy control individuals underwent three testing sessions on separate days. Briefly, 15 contact heat stimuli were delivered to the right hand dorsum, while the left palmar side of the hand was being conditioned with either neutral (32 °C), cool (20 °C), warm (40 °C), or TGI (20/40 °C). Rating of perception (numeric rating scale: 0–10) and evoked potentials (i.e., N1 and N2P2 potentials) to noxious contact heat stimuli were assessed. While cool and warm conditioning decreased cortical responses to noxious heat, TGI conditioning increased evoked potential amplitude (N1 and N2P2). In line with other modalities of unpleasant conditioning (e.g., sound, visual, and olfactory stimulation), cortical and possibly sub-cortical modulation may underlie the facilitation of contact heat evoked potentials.

Pupil responses and pain ratings to heat stimuli: Reliability and effects of expectations and a conditioning pain stimulus

BackgroundThe locus coeruleus (LC) signals salience to sensory stimuli and these responses can modulate the experience of pain stimuli. The pupil dilation response (PDR) to noxious stimuli is thought to be a surrogate for LC responses, but PDR response to Peltier-controlled noxious heat stimuli, the most commonly used method in experimental pain research, has not been described. New methodHealthy volunteers were presented with randomly presented heat stimuli of 5 sec duration and provided pain intensity ratings to each stimulus. Pupillometry was performed and a method developed to quantify the PDR relevant to these stimuli. The stimulus response, reliability, and effect of commonly used manipulations on pain experience were explored. ResultsA method of artifact removal and adjusting for lag from stimulus initiation to PDR response was developed, resulting in a close correlation between pain intensity rating and PDR across a large range of heat stimuli. A reliable assessment of PDR within an individual was achieved with fewer presentations as heat stimulus intensity increased. The correlation between pain rating and PDR was disrupted when cognitive load is increased by manipulating expectations or presenting a second pain stimulus. Comparison with existing methodsThe PDR began later after skin heating than electrical stimuli and this is the first examination of the PDR using standard nociceptive testing and manipulations of expectations and competing noxious stimulation. ConclusionsA method is described applying PDR to standard heat nociceptive testing, demonstrating stimulus response, reliability, and disruption by cognitive manipulation.

P1

The origin of the conscious experience of pain in the brain is a continuing enigma in neuroscience. To shed light on the brain representation of a multifaceted pain experience in humans, we combined multivariate analysis of subjective aspects of pain sensations with detailed, single-trial analysis of electrophysiological brain responses.Participants were asked to fully focus on any painful or non-painful sensations occurring in their left hand during an interval surrounding the onset of noxious laser heat stimuli, and to rate their sensations using a set of visual analogue scales. Statistical parametric mapping was used to compute a multivariate regression analysis of subjective responses and single-trial laser evoked potentials (LEPs) at subject and group levels. Standardized Low Resolution Electromagnetic Tomography method was used to reconstruct sources of LEPs.Factor analysis of subjective responses yielded five factors. Factor 1, representing pain, mapped firstly as a negative potential at the vertex and a positive potential at the fronto-temporal region during the 208–260 ms interval, and secondly as a strong negative potential in the right lateral frontal and prefrontal scalp regions during the 1292–1340 ms interval. Three other factors, labelled “anticipated pain”, “stimulus onset time”, and “body sensations”, represented non-specific aspects of the pain experience, and explained portions of LEPs in the latency range from 200 ms to 700 ms.The subjective space of pain during noxious laser stimulation is represented by one large factor featuring pain intensity, and by other factors accounting for non-specific parts of the sensory experience. Pain is encoded in two separate latency components with different scalp and brain representations.

Pain modulation by intranasal oxytocin and emotional picture viewing - a randomized double-blind fMRI study.

The hormone oxytocin has been hypothesized to influence the emotional dimension of pain. This randomized, placebo-controlled, double-blind, crossover study explored whether intranasal oxytocin and emotional context can affect heat pain perception in 30 healthy male volunteers. After receiving 36 IU oxytocin or placebo, participants underwent functional Magnetic Resonance Imaging (fMRI) during which noxious and non-noxious thermode heat stimuli were applied. Simultaneously, scenes from the International Affective Pictures System (IAPS) with positive, neutral, and negative emotional valence were shown. Heat intensity and unpleasantness ratings were obtained. The activity of whole-brain correlates of heat processing was quantified via multi-voxel pattern analysis. We observed no appreciable main effects of oxytocin on ratings or neural pain correlates. Effects of emotional picture valence on ratings were smaller than reported in previous studies. Nevertheless, oxytocin was found to significantly enhance the influence of picture valence on unpleasantness ratings at noxious heat levels. No corresponding changes in whole-brain correlates of heat intensity processing were found. Our study provides evidence that intranasal oxytocin increases the effects of emotional context on the subjective unpleasantness of experimental heat pain. Future studies are needed to determine whether this effect can be utilized in clinical settings.

Spatial and Temporal Brain Responses to Noxious Heat Thermal Stimuli in Burning Mouth Syndrome

Burning mouth syndrome (BMS) is an idiopathic orofacial pain condition. Although the pathophysiology of BMS is not clearly understood, central and peripheral neuropathic mechanisms are thought to be involved. The authors compared brain response to noxious heat stimuli in 16 right-handed women with primary BMS and 15 sex- and age-matched right-handed healthy female controls. A thermal stimulus sequence of 32 °C to 40 °C to 32 °C to 49 °C was repeated 4 times in a cycle. Warm and noxious heat stimuli were delivered with a Peltier thermode placed on the right palm or right lower lip for 32 s each in a session. Functional magnetic resonance imaging data were obtained by recording echoplanar images with a block design. Statistical Parametric Mapping 8 software was used to analyze the data. Patients and controls both reported feeling more pain during palm stimulation than during lip stimulation. Repetition of noxious heat stimulus on the lower lip but not on the palm induced habituation in brain activity in the cingulate cortex without reduction in pain perception. Multiple regression analysis revealed a correlation between perceived pain intensity and suppression of brain activity in the anterior cingulate cortex when the repeated thermal sequence was applied at the lower lip. Furthermore, the response of the parahippocampal area differed in BMS patients and controls when the same repeated thermal sequence was applied at the palm. The authors’ findings indicate that BMS patients show specific brain responses due to impaired function of the central and peripheral nervous systems (clinical trial registration: UMIN000015002).

Location, location, location: Variation in sensitivity to pain across the body.

There is evidence that sensitivity to noxious stimuli differs between the sexes and across the body, but few studies have investigated differences in the perception and experience of acute pain stimuli across the body in healthy individuals. We recruited 52 healthy participants, aged 18-36 (50% men) and administered 39, 42 and 45°C stimuli at four body sites bilaterally to examine differences in the experience of pain intensity and unpleasantness between body sites via an 11-point numerical rating scale. Noxious and innocuous thermal heat stimuli were perceived as significantly more intense when delivered to the wrist (M=3.98, SD = 1.93) and back (M =4.07, SD=1.98) compared to the shoulder (M=3.45, SD=1.91) and leg (M=3.46, SD=1.87). Pain unpleasantness ratings yielded similar findings; stimuli were perceived as more unpleasant when administered to the wrist (M=2.83, SD=1.93) and lower back (M=3.04, SD=2.11) compared to the shoulder (M=2.63, SD=1.85) and leg (M=2.26, SD=1.82). These findings suggest that painful thermal stimuli delivered to the wrist and back are perceived as more intense and unpleasant compared with other body sites in healthy persons. These differences may be due to variations in receptor density, or the relative importance of these sites for daily living and survival. Moreover, these insights are helpful for the design of studies investigating pain experience in healthy persons in experimental or clinical settings. WHAT DOES THIS STUDY ADD?: We tested sensitivity to acute suprathreshold thermal stimulations across a range of body sites to investigate for potential variability. We found significant differences in the perceived intensity and unpleasantness of noxious and innocuous thermal stimuli at the wrist and lower back, compared with the shoulder and leg. These results suggest that pain experience is driven by receptor density or the relative functional importance of these sites.

Interhemispheric Dorsolateral Prefrontal Cortex Connectivity is Associated with Individual Differences in Pain Sensitivity in Healthy Controls.

The dorsolateral prefrontal cortex (DLPFC) is implicated in pain modulation through multiple psychological processes. Recent noninvasive brain stimulation studies suggest that interhemispheric DLPFC connectivity influences pain tolerance and discomfort by altering interhemispheric inhibition. The structure and role of interhemispheric DLPFC connectivity in pain processing have not been investigated. The present study used dynamic causal modeling (DCM) for fMRI to investigate transcallosal DLPFC connectivity during painful stimulation in healthy volunteers. DCM parameters were used to predict individual differences in sensitivity to noxious heat stimuli. Bayesian model selection results indicated that influences among the right DLPFC (rDLPFC) and left DLPFC (lDLPFC) are modulated during painful stimuli. Regression analyses revealed that greater rDLPFC→lDLPFC couplings were associated with higher suprathreshold pain temperatures. These results highlight the role of interhemispheric connectivity in pain modulation and support the preferential role of the right hemisphere in pain processing. Knowledge of these mechanisms may improve understanding of abnormal pain modulation in chronic pain populations.

Calcitonin Gene-Related Peptide Modulates Heat Nociception in the Human Brain - An fMRI Study in Healthy Volunteers.

BackgroundIntravenous infusion of calcitonin-gene-related-peptide (CGRP) provokes headache and migraine in humans. Mechanisms underlying CGRP-induced headache are not fully clarified and it is unknown to what extent CGRP modulates nociceptive processing in the brain. To elucidate this we recorded blood-oxygenation-level-dependent (BOLD) signals in the brain by functional MRI after infusion of CGRP in a double-blind placebo-controlled crossover study of 27 healthy volunteers. BOLD-signals were recorded in response to noxious heat stimuli in the V1-area of the trigeminal nerve. In addition, we measured BOLD-signals after injection of sumatriptan (5-HT1B/1D antagonist).ResultsBrain activation to noxious heat stimuli following CGRP infusion compared to baseline resulted in increased BOLD-signal in insula and brainstem, and decreased BOLD-signal in the caudate nuclei, thalamus and cingulate cortex. Sumatriptan injection reversed these changes.ConclusionThe changes in BOLD-signals in the brain after CGRP infusion suggests that systemic CGRP modulates nociceptive transmission in the trigeminal pain pathways in response to noxious heat stimuli.

Phase 1 Safety Assessment of Intrathecal Oxytocin

Background Preclinical data suggest that oxytocin reduces hypersensitivity by actions in the spinal cord, but whether it produces antinociception to acute stimuli is unclear. In this article, the authors examined the safety of intrathecal oxytocin and screened its effects on acute noxious stimuli. Methods After institutional review board and Food and Drug Administration approval, healthy adult volunteers received 5, 15, 50, or 150 μg intrathecal oxytocin in a dose-escalating manner in cohorts of five subjects. Hemodynamic and neurologic assessments were performed for 4 h after injections and 24 h later, at which time serum sodium was also measured. Cerebrospinal fluid was obtained 60 min after injection, and responses to noxious heat stimuli in arm and leg as well as temporal summation to repeated application of a von Frey filament were obtained. Results One subject receiving the highest dose experienced transient hypotension and bradycardia as well as subjective numbness in a lumbo-sacral distribution. No other subject experienced subjective or objective neurologic symptoms. Overall, blood pressure and heart rate increased 1 to 4 h after injection by less than 15% with no dose dependency. There was no effect on serum sodium, and cerebrospinal fluid oxytocin increased in a dose-dependent manner after injection. Pain scores to noxious heat stimuli were unaffected by oxytocin, and the temporal summation protocol failed to show summation before or after drug treatment. Conclusion This small study supports further investigation on oxytocin for analgesia for hypersensitivity states, with continued systematic surveillance for possible effects on blood pressure, heart rate, and neurologic function.

Exercise Strengthens Central Nervous System Modulation of Pain in Fibromyalgia.

To begin to elucidate the mechanisms underlying the benefits of exercise for chronic pain, we assessed the influence of exercise on brain responses to pain in fibromyalgia (FM). Complete data were collected for nine female FM patients and nine pain-free controls (CO) who underwent two functional neuroimaging scans, following exercise (EX) and following quiet rest (QR). Brain responses and pain ratings to noxious heat stimuli were compared within and between groups. For pain ratings, there was a significant (p < 0.05) Condition by Run interaction characterized by moderately lower pain ratings post EX compared to QR (d = 0.39–0.41) for FM but similar to ratings in CO (d = 0.10–0.26), thereby demonstrating that exercise decreased pain sensitivity in FM patients to a level that was analogous to pain-free controls. Brain responses demonstrated a significant within-group difference in FM patients, characterized by less brain activity bilaterally in the anterior insula following QR as compared to EX. There was also a significant Group by Condition interaction with FM patients showing less activity in the left dorsolateral prefrontal cortex following QR as compared to post-EX and CO following both conditions. These results suggest that exercise appeared to stimulate brain regions involved in descending pain inhibition in FM patients, decreasing their sensitivity to pain. Thus, exercise may benefit patients with FM via improving the functional capacity of the pain modulatory system.

Normothermic Mouse Functional MRI of Acute Focal Thermostimulation for Probing Nociception

Combining mouse genomics and functional magnetic resonance imaging (fMRI) provides a promising tool to unravel the molecular mechanisms of chronic pain. Probing murine nociception via the blood oxygenation level-dependent (BOLD) effect is still challenging due to methodological constraints. Here we report on the reproducible application of acute noxious heat stimuli to examine the feasibility and limitations of functional brain mapping for central pain processing in mice. Recent technical and procedural advances were applied for enhanced BOLD signal detection and a tight control of physiological parameters. The latter includes the development of a novel mouse cradle designed to maintain whole-body normothermia in anesthetized mice during fMRI in a way that reflects the thermal status of awake, resting mice. Applying mild noxious heat stimuli to wildtype mice resulted in highly significant BOLD patterns in anatomical brain structures forming the pain matrix, which comprise temporal signal intensity changes of up to 6% magnitude. We also observed sub-threshold correlation patterns in large areas of the brain, as well as alterations in mean arterial blood pressure (MABP) in response to the applied stimulus.

Thermal Sensitivity and Dimethyl Sulfoxide (DMSO).

Dimethyl sulfoxide (DMSO) is commonly used as a solvent for hydrophobic substances, but the compound's innate bioactivity is an area of limited understanding. In this investigation we seek to determine the analgesic potential of DMSO. We addressed the issue by assessing the perception of thermal pain stimulus, using a 55°C hotplate design, in conscious mice. The latency of withdrawal behaviors over a range of incremental accumulative intraperitoneal DMSO doses (0.5-15.5g/kg) in the same mouse was taken as a measure of thermal endurance. The findings were that the latency, on average, amounted to 15-30s and it differed inappreciably between the sequential DMSO conditions. Nor was it different from the pre-DMSO control conditions. Thus, DMSO did not influence the cutaneous thermal pain perception. The findings do not lend support to those literature reports that point to the plausible antinociceptive potential of DMSO as one of a plethora of its innate bioactivities. However, the findings concern the mouse's footpad nociceptors which have specific morphology and stimulus transduction pathways, which cannot exclude DMSO's antinociceptive influence on other types of pain or in other types of skin. Complex and as yet unresolved neural mechanisms of perception of cutaneous noxious heat stimulus should be further explored with alternative experimental designs.

Mapping multidimensional pain experience onto electrophysiological responses to noxious laser heat stimuli

The origin of the conscious experience of pain in the brain is a continuing enigma in neuroscience. To shed light on the brain representation of a multifaceted pain experience in humans, we combined multivariate analysis of subjective aspects of pain sensations with detailed, single-trial analysis of electrophysiological brain responses.Participants were asked to fully focus on any painful or non-painful sensations occurring in their left hand during an interval surrounding the onset of noxious laser heat stimuli, and to rate their sensations using a set of visual analogue scales. Statistical parametric mapping was used to compute a multivariate regression analysis of subjective responses and single-trial laser evoked potentials (LEPs) at subject and group levels. Standardized Low Resolution Electromagnetic Tomography method was used to reconstruct sources of LEPs.Factor analysis of subjective responses yielded five factors. Factor 1, representing pain, mapped firstly as a negative potential at the vertex and a positive potential at the fronto-temporal region during the 208–260ms interval, and secondly as a strong negative potential in the right lateral frontal and prefrontal scalp regions during the 1292–1340ms interval. Three other factors, labelled “anticipated pain”, “stimulus onset time”, and “body sensations”, represented non-specific aspects of the pain experience, and explained portions of LEPs in the latency range from 200ms to 700ms.The subjective space of pain during noxious laser stimulation is represented by one large factor featuring pain intensity, and by other factors accounting for non-specific parts of the sensory experience. Pain is encoded in two separate latency components with different scalp and brain representations.

Evolving understanding on the aetiology of thermally provoked itch.

Background and objectivesItch is one of the major symptoms in dermatology clinics, and severely impairs the quality of life. Itch is frequently produced by environmental stimuli, especially heat or warmth. Changes of temperature on the skin surface and noxious heat stimuli augment and develop itch, respectively. Thermally provoked itch is sometimes intractable with existing treatments.Data bases and data treatmentRecent researches, linking heat sensation and itch, were searched in MEDLINE literature database through PubMed.ResultsRecent studies of the transient receptor potential cation channel subfamily vanilloid type 1 (TRPV1), the calcitonin gene‐related peptide (CGRP) and the vesicular glutamate transporter 2 (VGLUT2), which link noxious heat and itch, contribute to a much better understanding of the thermally evoked itch process. From a clinical perspective, a warm sensation is a major provocative factor for subjects with atopic dermatitis. The accumulation of artemin (also known as enovin or neublastin) in the dermis of lesional skin can possibly provide a pathological mechanism for warmth‐provoked itch.ConclusionsThis mini‐review describes recent results of both basic and clinical research related to thermally provoked itch.

Pain inhibits pain; human brainstem mechanisms

Conditioned pain modulation is a powerful analgesic mechanism, occurring when a painful stimulus is inhibited by a second painful stimulus delivered at a different body location. Reduced conditioned pain modulation capacity is associated with the development of some chronic pain conditions and the effectiveness of some analgesic medications. Human lesion studies show that the circuitry responsible for conditioned pain modulation lies within the caudal brainstem, although the precise nuclei in humans remain unknown. We employed brain imaging to determine brainstem sites responsible for conditioned pain modulation in 54 healthy individuals. In all subjects, 8 noxious heat stimuli (test stimuli) were applied to the right side of the mouth and brain activity measured using functional magnetic resonance imaging. This paradigm was then repeated. However, following the fourth noxious stimulus, a separate noxious stimulus, consisting of an intramuscular injection of hypertonic saline into the leg, was delivered (conditioning stimulus). During this test and conditioning stimulus period, 23 subjects displayed conditioned pain modulation analgesia whereas 31 subjects did not. An individual's analgesic ability was not influenced by gender, pain intensity levels of the test or conditioning stimuli or by psychological variables such as pain catastrophizing or fear of pain. Brain images were processed using SPM8 and the brainstem isolated using the SUIT toolbox. Significant increases in signal intensity were determined during each test stimulus and compared between subjects that did and did not display CPM analgesia (p<0.05, small volume correction). The expression of analgesia was associated with reduction in signal intensity increases during each test stimulus in the presence of the conditioning stimulus in three brainstem regions: the caudalis subdivision of the spinal trigeminal nucleus, i.e., the primary synapse, the region of the subnucleus reticularis dorsalis and in the dorsolateral pons in the region of the parabrachial nucleus. Furthermore, the magnitudes of these signal reductions in all three brainstem regions were significantly correlated to analgesia magnitude. Defining conditioned pain modulation circuitry provides a framework for the future investigations into the neural mechanisms responsible for the maintenance of persistent pain conditions thought to involve altered analgesic circuitry.

Inter-individual differences in pain processing investigated by functional magnetic resonance imaging of the brainstem and spinal cord

The experience of pain is a highly complex and personal experience, characterized by tremendous inter-individual variability. The purpose of this study was to use functional magnetic resonance imaging (fMRI) to characterize responses in the brainstem and spinal cord to the same heat stimulus in healthy participants, to further our understanding of individual differences in pain perception. Responses to noxious heat stimuli at 49°C were investigated in 20 healthy individuals by means of fMRI of the brainstem and spinal cord, at 3Tesla, and were compared with brain fMRI and quantitative sensory testing. Blood oxygenation-level dependent (BOLD) responses were detected with a general linear model (GLM) and effective connectivity was examined with structural equation modeling (SEM). Reported pain ratings ranged from 18 to 84/100 across the participants. Consistent with previous research, brain fMRI results show that BOLD responses in a number of cortical regions are correlated with individual pain ratings. Correlations between pain scores and BOLD responses are also demonstrated in the spinal cord dorsal horn, locus coeruleus, and thalamus. SEM results demonstrate the network of brainstem and spinal cord regions that contribute to the pain response, and reveal differences related to individual pain sensitivity. The results of this study are consistent with the conclusion that individual differences in pain perception in healthy participants are a consequence of differences in descending modulation of spinal nociceptive processes from brainstem regions.

Differential fMRI Activation Patterns to Noxious Heat and Tactile Stimuli in the Primate Spinal Cord.

Mesoscale local functional organizations of the primate spinal cord are largely unknown. Using high-resolution fMRI at 9.4 T, we identified distinct interhorn and intersegment fMRI activation patterns to tactile versus nociceptive heat stimulation of digits in lightly anesthetized monkeys. Within a spinal segment, 8 Hz vibrotactile stimuli elicited predominantly fMRI activations in the middle part of ipsilateral dorsal horn (iDH), along with significantly weaker activations in ipsilateral (iVH) and contralateral (cVH) ventral horns. In contrast, nociceptive heat stimuli evoked widespread strong activations in the superficial part of iDH, as well as in iVH and contralateral dorsal (cDH) horns. As controls, only weak signal fluctuations were detected in the white matter. The iDH responded most strongly to both tactile and heat stimuli, whereas the cVH and cDH responded selectively to tactile versus nociceptive heat, respectively. Across spinal segments, iDH activations were detected in three consecutive segments in both tactile and heat conditions. Heat responses, however, were more extensive along the cord, with strong activations in iVH and cDH in two consecutive segments. Subsequent subunit B of cholera toxin tracer histology confirmed that the spinal segments showing fMRI activations indeed received afferent inputs from the stimulated digits. Comparisons of the fMRI signal time courses in early somatosensory area 3b and iDH revealed very similar hemodynamic stimulus-response functions. In summary, we identified with fMRI distinct segmental networks for the processing of tactile and nociceptive heat stimuli in the cervical spinal cord of nonhuman primates. Significance statement: This is the first fMRI demonstration of distinct intrasegmental and intersegmental nociceptive heat and touch processing circuits in the spinal cord of nonhuman primates. This study provides novel insights into the local functional organizations of the primate spinal cord for pain and touch, information that will be valuable for designing and optimizing therapeutic interventions for chronic pain management.

Anatomical evidence that the uninjured adjacent L4 nerve plays a significant role in the development of peripheral neuropathic pain after L5 spinal nerve ligation in rats

ABSTRACTRats develop hyperalgesia and allodynia in the hind paw after L5 spinal nerve ligation. Phosphorylated extracellular regulated kinase (pERK) was used as a pain marker to investigate the potential role of adjacent uninjured L4 nerve in the development of heat hyperalgesia after L5 nerve injury. Left L5 nerve was ligated and sectioned in rats. Three days later, rats were randomly assigned to five groups; each had both hind paws immersed in water at different temperatures (no heat, 37, 42, 47, and 52°C) under sevoflurane anesthesia for 2 minutes. Five minutes after stimulation the rats were sacrificed and sections of L3–L6 spinal segments were stained immunocytochemically with pERK antibody. pERK immunoreactivity, which is not detectable in the normal spinal cord, was discernible in neurons (not glia) of the superficial dorsal horn after noxious heat stimuli. pERK‐positive neurons clearly overlapped in laminae I–II with normal unmyelinated and thin myelinated afferents labeled with calcitonin gene‐related peptide and isolectin B4, and injured unmyelinated afferents labeled with vasoactive intestinal polypeptide. There was a linear increase in pERK immunoreactivity on both sides with an increase in temperature. Importantly, the number of positive pERK neurons was significantly higher in the ipsilateral side of L4 spinal segment, which receives innervation from uninjured L4 nerve, compared with the contralateral control side, which receives both uninjured L4 and L5 spinal nerves. The data demonstrate that the uninjured L4 nerve plays an important role in the development of heat hyperalgesia at the spinal cord level after L5 nerve injury. J. Comp. Neurol. 523:1731–1747, 2015. © 2015 Wiley Periodicals, Inc.