Responses of trigeminal subnucleus interpolaris neurons to afferent inputs from deep oral structures.

Responses of trigeminal subnucleus interpolaris neurons to natural and electrical stimulation of the temporomandibular joint (TMJ) and the masseter muscle (Mm) were studied in the anesthetized rat. Interpolaris neurons could be placed in one of three classes determined by their responses to noxious and innocuous stimuli: Class I, excited by only innocuous stimuli; Class II, excited by only noxious stimuli; Class III, excited by both. In each class, the conduction velocities of the primary afferents were roughly equivalent to those of small-diameter fibers. Approximately 70% of the interpolaris neurons tested received nociceptive inputs from the TMJ and/or the Mm. Most of these neurons had extensive convergence of afferent inputs, including the TMJ, the Mm, and/or the facial skin. The results suggest involvement of interpolaris neurons in the characteristics of deep pain, such as its spread and referral.     

Somatosensory cortex: A comparison of the response to noxious thermal,mechanical, and electrical stimuli using functional magnetic resonance imaging

In the present study, functional magnetic resonance imaging (fMRI) was used to examine pain perception in humans. Three types of noxious stimuli were presented: electric shock (20.8 mA, 2 Hz), heat (48°C), and mechanical, as well as a control tactile stimulus. The significance of activation at the level of the voxel was determined using correlation analysis. Significant region of interest (ROI) activation was determined by comparing the percentage of active voxels in each ROI to activation in a control ROI in the visual cortex. In response to tactile and shock stimuli, consistent activation was seen in the postcentral gyrus, parietal operculum, and ipsilateral cerebellar cortex. No significant cortical activation was detected in response to noxious heat or mechanical stimulation when compared to nonpainful intensity levels. The data did not indicate adaptation, although further study in this area is necessary. Stationary noxious thermal and mechanical stimulation are “pure” noxious stimuli, while electrical stimulation influenced nociceptive and nonnociceptive receptors. Lack of detectable activation in response to pure noxious stimuli supports the idea that nociceptive and nonnociceptive fibers are interspersed in the somatosensory cortex. Conflicting results from recent functional imaging studies of pain perception regarding cortical activation indicate that it is essential to consider both the tactile and nociceptive components of the stimuli used, the spatial extent of stimulation, and the possibility of adaptation to the response. Furthermore, these results suggest that subtractive or correlative methods may not be sufficiently sensitive to image the activity of nociceptive cells, which are sparsely distributed throughout the somatosensory cortex. Hum. Brain Mapping 6:150–159, 1998. © 1998 Wiley-Liss, Inc.     

Cortical representation of pain in primary sensory‐motor areas (S1/M1)—a study using intracortical recordings in humans

Intracortical evoked potentials to nonnoxious Aβ (electrical) and noxious Aδ (laser) stimuli within the human primary somatosensory (S1) and motor (M1) areas were recorded from 71 electrode sites in 9 epileptic patients. All cortical sites responding to specific noxious inputs also responded to nonnoxious stimuli, while the reverse was not always true. Evoked responses in S1 area 3b were systematic for nonnoxious inputs, but seen in only half of cases after nociceptive stimulation. Nociceptive responses were systematically recorded when electrode tracks reached the crown of the postcentral gyrus, consistent with an origin in somatosensory areas 1–2. Sites in the precentral cortex also exhibited noxious and nonnoxious responses with phase reversals indicating a local origin in area 4 (M1). We conclude that a representation of thermal nociceptive information does exist in human S1, although to a much lesser extent than the nonnociceptive one. Notably, area 3b, which responds massively to nonnoxious Aβ activation was less involved in the processing of noxious heat. S1 and M1 responses to noxious heat occurred at latencies comparable to those observed in the supra‐sylvian opercular region of the same patients, suggesting a parallel, rather than hierarchical, processing of noxious inputs in S1, M1 and opercular cortex. This study provides the first direct evidence for a spinothalamic related input to the motor cortex in humans. Hum Brain Mapp 34:2655–2668, 2013. © 2012 Wiley Periodicals, Inc.     

Selective inhibition by systemic lidocaine of noxious evoked activity in rat dorsal horn neurons

The effect of systemically injected lidocaine (3-4 mg kg-1) on the responses to noxious and non-noxious stimuli on 28 wide dynamic range (WDR) neurons in the dorsal horn was studied in anesthetized and curarized rats. It was consistently found that lidocaine reduced or suppressed the responses to noxious stimuli whereas it did not act on the responses to non-noxious stimulation and on the spontaneous activity. Furthermore the noxious stimuli were completely ineffective from 10-15 min following the lidocaine injection while the non-noxious stimuli maintained their efficacy. The control responses, in all the cases, returned within 20 min. The results suggest that lidocaine exerts a selective inhibitory effect on nociceptive transmission at the spinal level.     

Neural activity related to self- versus externally generated painful stimuli reveals distinct differences in the lateral pain system in a parametric fMRI study

Self-generated sensory stimulation can be distinguished from externally generated stimulation that is otherwise identical. To determine how the brain differentiates external from self-generated noxious stimulation and which structures of the lateral pain system use neural signals to predict the sensory consequences of self-generated painful stimulation, we used functional magnetic resonance imaging to examine healthy human subjects who received thermal-contact stimuli with noxious and non-noxious temperatures on the resting right hand in random order. These stimuli were internally (self-generated) or externally generated. Two additional conditions served as control conditions: to account for stimulus onset uncertainty, acoustic stimuli preceding the same thermal stimuli were used with variable or fixed delays but without any stimulus-eliciting movements. Whereas graded pain-related activity in the insula and secondary somatosensory cortex (SII) was independent of how the stimulus was generated, it was attenuated in the primary somatosensory cortex (SI) during self-generated stimulation. These data agree with recent concepts of the parallel processing of nociceptive signals to the primary and secondary somatosensory cortices. They also suggest that brain areas that encode pain intensity do not distinguish between internally or externally applied noxious stimuli, i.e., this adaptive biological mechanism prevents harm to the individual. The attenuated activation of SI during self-generated painful stimulation might be a result of the predictability of the sensory consequences of the pain-related action.     

Pain processing within the primary somatosensory cortex in humans

To investigate the processing of noxious stimuli within the primary somatosensory cortex (SI), we recorded magnetoencephalography following noxious epidermal electrical stimulation (ES) and innocuous transcutaneous electrical stimulation (TS) applied to the dorsum of the left hand. TS activated two sources sequentially within SI: one in the posterior bank of the central sulcus and another in the crown of the postcentral gyrus, corresponding to Brodmann's areas 3b and 1, respectively. Activities from area 3b consisted of 20- and 30-ms responses. Activities from area 1 consisted of three components peaking at 26, 36 and 49 ms. ES activated one source within SI whose location and orientation were similar to those of the TS-activated area 1 source. Activities from this source consisted of three components peaking at 88, 98 and 109 ms, later by 60 ms than the corresponding TS responses. ES and TS subsequently activated a similar region in the upper bank of the sylvian fissure, corresponding to the secondary somatosensory cortex (SII). The onset latency of the SII activity following ES (109 ms) was later by 29 ms than that of the first SI response (80 ms). Likewise, the onset latency of SII activity following TS (52 ms) was later by 35 ms than that of area 1 of SI (17 ms). Therefore, our results showed that the processing of noxious and innocuous stimuli is similar with respect to the source locations and activation timings within SI and SII except that there were no detectable activations within area 3b following noxious stimulation.     

Drastic changes of ventromedial medulla neuronal properties induced by barbiturate anesthesia. I. Comparison of the single-unit types in the same awake and pentobarbital-treated rats.

By means of single-unit recordings, as we have already performed in other studies, we have found that in the awake, drug-free, freely moving rat, there is only one neuronal class potentially involved in nociception and its control at the ventromedial medulla level (VMM, a structure involved in the spinal descending control systems of nociception): the 'multireceptive multimodal' units. These neurons are always activated by very light mechanical (air puff, light touch) and mechanical (pinch, pin-prick) or thermal noxious stimuli, in addition to an auditory stimulus. During identical VMM penetrations, performed in the same animals tested first awake and then anesthetized a few days later with 30 mg/kg of i.p. pentobarbital, we once again found the 'multireceptive multimodal' units, but this time with physiological properties that were strongly modified: in particular, we noted a disappearance of the nociceptive responses consecutive to a strong noxious heat pulse application (36-51 degrees C), associated sometimes with a reduction of the responses due to innocuous stimulation. This is in agreement with the classical effects of barbiturates. In light of previous observations reported in the literature devoted to the VMM physiology in the anesthetized rat, the most important observation in our study was that, with pentobarbital anesthesia, we recorded 'new' neuronal classes as compared to the awake condition. In these classes, which appeared to be qualitatively similar to those already reported under anesthesia, we found the units exclusively driven by innocuous stimulation (excited for the majority), the units specifically driven by noxious stimulation (half excited, half inhibited) and a 'multireceptive multimodal' group inhibited or excited-inhibited by non-noxious and noxious stimuli (half of the multireceptive group). All these data demonstrate that barbiturate anesthesia strongly modifies the VMM physiology in relation to nociception. Furthermore, since our results, that were obtained in anesthetized rats, were qualitatively identical to those described in the literature under similar experimental conditions, they raise the question of the appropriateness of using a barbiturate anesthetic in order to study the cellular mechanisms related to nociception at this level. In addition, these findings indicate that the obtention of only one neuronal class in the awake, drug-free, freely moving rat (the excited 'multireceptive' neurons) is not due to an experimental bias, which strongly emphasizes the reliability of using awake animals. However, it remains to be determined by which mechanisms pentobarbital 'distorts' the VMM physiology as compared to the normal, standard physiological conditions of the awake animal.     

Nonsegmental inhibition of rat dorsal horn neurons by innocuous stimulation

In rats anesthetized with thiamylal sodium, responses of spinal cord dorsal horn neurons to noxious skin heating of the tail were recorded by extracellular microelectrodes. Inhibition of these responses by innocuous mechanical stimulation (light brushing) of the ipsilateral forelimb was assessed. Short-lasting application (3 min, or less) of light brushing did not inhibit neuronal responses to noxious heating. Long-lasting application (5 min, or more) inhibited responses of these neurons to noxious stimulation. The results indicate that, in the anesthetized rat, remotely applied innocuous cutaneous stimuli can inhibit nociceptive responses of dorsal horn neurons, if applied for a sufficiently long time.     

Responses of neurons in ventroposterolateral nucleus of primate thalamus to urinary bladder distension.

The purpose of this study was to examine effects of a noxious visceral stimulus, urinary bladder distension (UBD), on cells in the ventroposterolateral (VPL) nucleus of anesthetized monkeys. We hypothesized that processing of visceral information in the VPL nucleus of the thalamus is similar to spinothalamic tract (STT) organization of visceral afferent input. Urinary bladder distension excites sacral and upper-lumbar STT cells that have somatic input from proximal somatic fields; whereas, thoracic STT cells are inhibited by UBD. Extracellular action potentials of 67 neurons were recorded in VPL nucleus. Urinary bladder distension excited 22 cells, inhibited 9 cells, and did not affect activity of 36 cells. Seventeen of 22 cells excited by UBD also received convergent somatic input from noxious squeeze of the hip, groin, or perineal regions. No cells activated only by innocuous somatic stimuli were excited by UBD. Five of 9 cells inhibited by UBD had upper-body somatic fields. There was a significant tendency for VPL neurons excited by UBD to have proximal lower-body somatic fields that were excited by noxious stimulation of skin and underlying muscle (P less than 0.001). Antidromic activation of 4 thalamic neurons affected by UBD showed that visceral input stimulated by UBD reached the primary somatosensory (SI) cortex.     

Dorsal column postsynaptic neurons in the cat are excited by myelinated nociceptors

Some (25-50%) dorsal column postsynaptic (DCPS) neurons respond only to innocuous mechanical stimuli; the remainder (50-75%) responds to both innocuous and noxious mechanical stimuli. Those that respond to noxious mechanical stimuli (pinch) are assumed to be excited by input from nociceptive primary afferents, but it is conceivable that their pinch-evoked responses are produced by the inadvertent activation of those low-threshold mechanoreceptive primary afferents that respond to stretching the skin. Because nociceptive primary afferents respond reliably to noxious heat and low-threshold mechanoreceptors do not, we tested DCPS neurons in the cat lumbar spinal cord with a series of noxious heat stimuli (48 degrees C or 50 degrees C-56 degrees C; 30 s duration). Seven of eight pinch-responsive neurons responded to noxious heat, but only after their receptive fields had been sensitized by prolonged or repeated heating. The results show that (1) many DCPS neurons in the cat are excited by nociceptive primary afferents and (2) these nociceptive afferents are probably myelinated high-threshold mechanoreceptors.     

Submodality-Selective Hyperalgesia Adjacent to Partially Injured Sciatic Nerve in the Rat is Dependent on Capsaicin-Sensitive Afferent Fibers and Independent of Collateral Sprouting or a Dorsal Root Reflex

We studied submodality dependence of sensory changes produced by unilateral ligation of the sciatic or the saphenous nerve in the rat. We focused especially on sensory changes in the skin area adjacent to the innervation area of the injured nerve. Moreover, we examined the roles of capsaicin-sensitive nociceptive fibers, collateral sprouting and a dorsal root reflex in sensory changes observed behaviorally. Assessment of sensory changes was performed by a pattern of behavioral tests: hot-plate test and hindlimb withdrawal responses induced by radiant heat, hot-water bath, innocuous mechanical stimuli, and noxious mechanical stimuli. In one group, the saphenous nerve ipsilateral to the sciatic ligation was topically treated with capsaicin (1%) at the time of the surgery. A proximal stump of a saphenous nerve strand was orthodromically stimulated to induce a dorsal root reflex (an antidromic volley) in nociceptive fibers of the saphenous nerve trunk. For visualization of plasma extravasation induced by a dorsal root reflex, a dye-labeling (Evans blue) technique was used. A collateral sprouting of nociceptive fibers of the uninjured saphenous nerve was evaluated by determining the plasma extravasation response induced by antidromic stimulation of the saphenous nerve. Three and 10 days following the sciatic constriction injury, the hindlimb withdrawal threshold evoked by noxious mechanical stimulation of the medial side of the paw (the innervation are of the intact saphenous nerve) was significantly decreased. There was no corresponding thermal hyperalgesia adjacent to the injured sciatic nerve. Chronic constriction of the saphenous nerve did not produce any significant hyper- or hypoalgesia to mechanical or thermal stimulation of the uninjured sciatic nerve area. Topical treatment of the ipsilateral (intact) saphenous nerve at the time of the sciatic nerve ligation completely prevented the development of mechanical hyperalgesia in the medial side of the paw (the innervation area of the saphenous nerve). No dorsal root reflex in nociceptive fibers mediating the adjacent hyperalgesia could be evoked. No collateral sprouting of the uninjured nociceptive fibers of the saphenous nerve was observed. The results indicate that the constriction injury of the sciatic nerve produced a selective hyperalgesia to mechanical stimulation in the innervation area of the neighboring saphenous nerve. At the peripheral level, the mechanical hyperalgesia adjacent to the innervation area of the injured nerve was mediated by capsaicin-sensitive nociceptive fibers. Collateral sprouting of nociceptive fibers from the uninjured to the injured innervation area did not contribute to the present sensory findings. The sciatic nerve injury did not induce a dorsal root reflex in nociceptive fibers innervating the hyperalgesic saphenous nerve area.     

Corticofugal influences on thalamic neurons during nociceptive transmission in awake rats

Pain is a multidimensional phenomenon and processed in a neural network. The supraspinal, brain mechanisms are increasingly recognized in playing a major role in the representation and modulation of pain. The aim of the current study is to investigate the functional interactions between cortex and thalamus during nociceptive processing, by observing the pain-related information flow and neuronal correlations within thalamo-cortical pathways. Pain-evoked, single-neuron activity was recorded in awake Sprague-Dawley rats with a Magnet system. Eight-wire microarrays were implanted into four different brain regions, i.e., the primary somatosensory (SI) and anterior cingulate cortex (ACC), as well as ventral posterior (VP) and medial dorsal thalamus (MD). Noxious radiant heat was delivered to the rat hind paws on the side contralateral to the recording regions. A large number of responsive neurons were recorded in the four brain areas. Directed coherence analysis revealed that the amount of information flow was significantly increased from SI cortex to VP thalamus following noxious stimuli, suggesting that SI cortex has descending influence on thalamic neurons during pain processing. Moreover, more correlated neuronal activities indicated by crosscorrelation histograms were found between cortical and thalamic neurons, with cortical neurons firing ahead of thalamic units. On basis of the above findings, we propose that nociceptive responses are modulated by corticothalamic feedback during nociceptive transmission, which may be tight in the lateral pathway, while loose in the medial pathway.     

BOLD responses in somatosensory cortices better reflect heat sensation than pain

The discovery of cortical networks that participate in pain processing has led to the common generalization that blood oxygen level-dependent (BOLD) responses in these areas indicate the processing of pain. Physical stimuli have fundamental properties that elicit sensations distinguishable from pain, such as heat. We hypothesized that pain intensity coding may reflect the intensity coding of heat sensation during the presentation of thermal stimuli during fMRI. Six 3T fMRI heat scans were collected for 16 healthy subjects, corresponding to perceptual levels of "low innocuous heat," "moderate innocuous heat," "high innocuous heat," "low painful heat," "moderate painful heat," and "high painful heat" delivered by a contact thermode to the face. Subjects rated pain and heat intensity separately after each scan. A general linear model analysis detected different patterns of brain activation for the different phases of the biphasic response to heat. During high painful heat, the early phase was associated with significant anterior insula and anterior cingulate cortex activation. Persistent responses were detected in the right dorsolateral prefrontal cortex and inferior parietal lobule. Only the late phase showed significant correlations with perceptual ratings. Significant heat intensity correlated activation was identified in contralateral primary and secondary somatosensory cortices, motor cortex, and superior temporal lobe. These areas were significantly more related to heat ratings than pain. These results indicate that heat intensity is encoded by the somatosensory cortices, and that pain evaluation may either arise from multimodal evaluative processes, or is a distributed process.     

Response properties of nociceptive and low-threshold mechanoreceptive neurons in the hamster superior colliculus

There are many somatosensory neurons in the hamster superior colliculus (SC); some respond to innocuous tactile stimuli, while others respond either preferentially, or solely, to noxious stimuli. Yet, there are little quantitative data describing the responses of these neurons. We sought to provide such information by relating stimulus intensity to the magnitude of the neural response using controlled innocuous and noxious mechanical and thermal stimuli. Of 122 somatosensory SC neurons studied in urethane-anesthetized hamsters, the majority (52%) had low-threshold mechanoreceptive properties (LT). LT neurons had force thresholds less than 1 gm, adapted rapidly to maintained stimuli, and did not respond with higher numbers of impulses to noxious mechanical or thermal stimuli. A smaller, though substantial, proportion of neurons (45%) responded either preferentially, or solely, to noxious stimuli. A few neurons (3%) were inhibited by either light tactile or noxious mechanical stimuli. Two populations of nociceptive neurons were found and classified either as wide dynamic range (WDR) neurons (n = 25), those that responded to gentle mechanical, noxious mechanical, and/or thermal stimuli; or nociceptive-specific (NS) neurons (n = 30), those that responded solely to high-intensity mechanical or noxious thermal stimuli. WDR neurons responded monotonically to increases in the intensity of innocuous mechanical stimuli, and displacement-response relationship for this population was a slightly negatively accelerating power function with an exponent of 0.785. However, the thermal stimulus-response relationships (to graded skin temperatures) of both WDR and NS neurons were positively accelerating power functions with exponents of 2.3 and 2.5 (r2 = 0.988), respectively. These values are consistent with both electrophysiological data from dorsal horn nociceptive neurons and from human psychophysical results using the same range of thermal stimuli. These experiments demonstrate that SC neurons are capable of signaling not only the presence and location of a noxious stimulus but its intensity as well. Presumably, these neurons play a significant role in the animal's reactions to potentially harmful stimuli. The partial laminar segregation of WDR and NS neurons may reflect different involvements of particular nociceptive subtypes in the various overt responses mediated by the SC.     

Effects of capsaicin applied to a peripheral nerve on the responses of primate spinothalamic tract cells

Capsaicin is a neurotoxin that appears to affect unmyelinated nociceptive sensory fibers selectively. We examined the effects of capsaicin applied topically to the sural nerve on peripheral nerve volleys and on the responses of neurons belonging to the spinothalamic tract (STT) in the monkey. The responses examined included those following electrical stimulation of the sural nerve and also those produced by more natural forms of noxious and innocuous stimuli applied to the skin. Capsaicin (1% solution) applied onto the sural nerve for 15 min resulted in a reduction of the sizes of A delta- and C-fiber afferent volleys. These changes paralleled the reduction of A- and C-fiber responses of the STT cells elicited by electrical stimulation of the sural nerve. During capsaicin application onto the sural nerve, the background activity of STT cells increased for 5-10 min. After capsaicin treatment, the responses of STT cells to innocuous mechanical stimuli applied to the cutaneous receptive field were increased, whereas the responses to noxious mechanical stimuli were decreased. However, topical capsaicin application almost eliminated the responses of STT cells to noxious heat stimuli. The results of the present study suggest that topical capsaicin application onto a peripheral nerve produces a transient nociceptive response followed by a decrease in sensitivity to noxious stimuli, particularly to noxious heat. These changes are due to conduction block of the nerve fibers at the site of capsaicin application.     

Intracortical modulation,and not spinal inhibition,mediates placebo analgesia

Suppression of spinal responses to noxious stimulation has been detected using spinal fMRI during placebo analgesia, which is therefore increasingly considered a phenomenon caused by descending inhibition of spinal activity. However, spinal fMRI is technically challenging and prone to false‐positive results. Here we recorded laser‐evoked potentials (LEPs) during placebo analgesia in humans. LEPs allow neural activity to be measured directly and with high enough temporal resolution to capture the sequence of cortical areas activated by nociceptive stimuli. If placebo analgesia is mediated by inhibition at spinal level, this would result in a general suppression of LEPs rather than in a selective reduction of their late components. LEPs and subjective pain ratings were obtained in two groups of healthy volunteers – one was conditioned for placebo analgesia while the other served as unconditioned control. Laser stimuli at three suprathreshold energies were delivered to the right hand dorsum. Placebo analgesia was associated with a significant reduction of the amplitude of the late P2 component. In contrast, the early N1 component, reflecting the arrival of the nociceptive input to the primary somatosensory cortex (SI), was only affected by stimulus energy. This selective suppression of late LEPs indicates that placebo analgesia is mediated by direct intracortical modulation rather than inhibition of the nociceptive input at spinal level. The observed cortical modulation occurs after the responses elicited by the nociceptive stimulus in the SI, suggesting that higher order sensory processes are modulated during placebo analgesia.     

Involvement of ventromedial medulla "multimodal, multireceptive" neurons in opiate spinal descending control system: a single-unit study of the effect of morphine in the awake, freely moving rat.

In the present work, we have studied the effects of systemic morphine on the electrophysiological properties of ventromedial medulla (VMM) neurons in the awake, freely moving rat. By means of a chronically implanted single-unit recording device, a drug delivery catheter, and the use of controlled innocuous and noxious cutaneous stimuli, we were able to study precisely the spontaneous and evoked VMM neuronal activities. We have particularly focused our attention upon the VMM "multimodal, multireceptive" units, excited by non-noxious and noxious stimuli (VMM MULT ON), which we have already determined as the neuronal class potentially involved in nociceptive processes at VMM level. We found that morphine (3 mg/kg, i.v.) does not affect the spontaneous activity of these neurons whereas their responses to noxious heat are strongly attenuated (70%), over a prolonged period (about 2 hr) associated with an increase in the response latency. This action of morphine appears to be pharmacologically specific since it is dose dependent to some extent, and is reversed by 0.3 mg/kg of naloxone. In parallel with this pharmacological specificity, we have also demonstrated a preferential physiological effect since the response of the VMM MULT ON neurons to light touch application is not affected by morphine. This specificity is emphasized by the fact that morphine does not modify the activity of the other VMM neuronal groups such as the units unresponsive to any kind of peripheral stimuli, and does not reveal "new" neuronal classes such as those we have found in previous studies after barbiturate administration. The differential effect upon the noxious versus innocuous inputs of these units produced by the opiate reinforces their participation in nociceptive processing since similar effects have been reported in well-known nociceptive somatosensory structures such as the dorsal horn of the spinal cord. Furthermore, although the precise mechanisms of action have not yet been determined, the spinal projection of the VMM MULT ON neurons, previously demonstrated by our group, suggests their involvement in an opiate descending spinal control system of nociception. Although speculative, one can imagine either a direct facilitatory MULT ON spinal effect being attenuated by morphine (disfacilitation), or a morphine-induced disinhibition of inhibitory GABAergic neurons acting upon the MULT ON neurons.     

Pain perception and response: central nervous system mechanisms

Although several decades of studies have detailed peripheral and ascending nociceptive pathways to the thalamus and cerebral cortex, pain is a symptom that has remained difficult to characterize anatomically and physiologically. Positron emission tomography (PET) and functional magnetic imaging (fMRI) have recently demonstrated a number of cerebral and brain stem loci responding to cutaneous noxious stimuli. However, intersubject variability, both in the frequency and increased or decreased intensity of the responses, has caused uncertainty as to their significance. Nevertheless, the large number of available imaging studies have shown that many areas with recognized functions are frequently affected by painful stimuli. With this evidence and recent developments in tracing central nervous system connections between areas responding to noxious stimuli, it is possible to identify nociceptive pathways that are within, or contribute to, afferent spino-thalamo-cortical sensory and efferent skeletomotor and autonomic motor systems. In this study it is proposed that cortical and nuclear mechanisms for pain perception and response are hierarchically arranged with the prefrontal cortex at its highest level. Nevertheless, all components make particular contributions without which certain nociceptive failures can occur, as in pathological pain arising in some cases of nervous system injury.     

Seeing touch and pain in a stranger modulates the cortical responses elicited by somatosensory but not auditory stimulation

Viewing other's pain inhibits the excitability of the motor cortex and also modulates the neural activity elicited by a concomitantly delivered nociceptive somatosensory stimulus. As the neural activity elicited by a transient nociceptive stimulus largely reflects non nociceptive‐specific, multimodal neural processes, here we tested, for the first time, whether the observation of other's pain preferentially affects the brain responses elicited by nociceptive stimulation, or instead similarly modulates those elicited by stimuli belonging to a different sensory modality. Using 58‐channel electroencephalography (EEG), we recorded the cortical responses elicited by laser and auditory stimulation during the observation of videoclips showing either noxious or non‐noxious stimulation of a stranger's hand. We found that the observation of other's pain modulated the cortical activity consisting in an event‐related desynchronization in the β band (β ERD), and elicited by nociceptive laser stimuli, but not by auditory stimuli. Using three different source analysis approaches, we provide converging evidence that such modulation affected neural activity in the contralateral primary sensorimotor cortex. The magnitude of this modulation correlated well with a subjective measure of similarity between the model's hand and the onlooker's representation of the hand. Altogether, these findings demonstrate that the observation of other's pain modulates, in a somatosensory‐specific fashion, the cortical responses elicited by nociceptive stimuli in the sensorimotor cortex contralateral to the stimulated hand. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.     

Motor Cortex Stimulation Suppresses Cortical Responses to Noxious Hindpaw Stimulation After Spinal Cord Lesion in Rats

BackgroundMotor cortex stimulation (MCS) is a potentially effective treatment for chronic neuropathic pain. The neural mechanisms underlying the reduction of hyperalgesia and allodynia after MCS are not completely understood.ObjectiveTo investigate the neural mechanisms responsible for analgesic effects after MCS. We test the hypothesis that MCS attenuates evoked blood oxygen-level dependent signals in cortical areas involved in nociceptive processing in an animal model of chronic neuropathic pain.MethodsWe used adult female Sprague–Dawley rats (n = 10) that received unilateral electrolytic lesions of the right spinal cord at the level of C6 (SCL animals). In these animals, we performed magnetic resonance imaging (fMRI) experiments to study the analgesic effects of MCS. On the day of fMRI experiment, 14 days after spinal cord lesion, the animals were anesthetized and epidural bipolar platinum electrodes were placed above the left primary motor cortex. Two 10-min sessions of fMRI were performed before and after a session of MCS (50 μA, 50 Hz, 300 μs, for 30 min). During each fMRI session, the right hindpaw was electrically stimulated (noxious stimulation: 5 mA, 5 Hz, 3 ms) using a block design of 20 s stimulation off and 20 s stimulation on. A general linear model-based statistical parametric analysis was used to analyze whole brain activation maps. Region of interest (ROI) analysis and paired t-test were used to compare changes in activation before and after MCS in these ROI.ResultsMCS suppressed evoked blood oxygen dependent signals significantly (Family-wise error corrected P < 0.05) and bilaterally in 2 areas heavily implicated in nociceptive processing. These areas consisted of the primary somatosensory cortex and the prefrontal cortex.ConclusionsThese findings suggest that, in animals with SCL, MCS attenuates hypersensitivity by suppressing activity in the primary somatosensory cortex and prefrontal cortex.