Characterization of chronic pain and somatosensory function in spinal cord injury subjects

The pathophysiology of the chronic pain following spinal cord injury (SCI) is unclear. In order to study it's underlying mechanism we characterized the neurological profile of SCI subjects with (SCIP) and without (SCINP) chronic pain. Characterization comprised of thermal threshold testing for warmth, cold and heat pain and tactile sensibility testing of touch, graphesthesia and identification of speed of movement of touch stimuli on the skin. In addition, spontaneously painful areas were mapped in SCIP and evoked pathological pain--allodynia, hyperpathia and wind-up pain evaluated for both groups. Both SCIP and SCINP showed similar reductions in both thermal and tactile sensations. In both groups thermal sensations were significantly more impaired than tactile sensations. Chronic pain was present only in skin areas below the lesion with impaired or absent temperature and heat-pain sensibilities. Conversely, all the thermally impaired skin areas in SCIP were painful while painfree areas in the same subjects were normal. In contrast, chronic pain could be found in skin areas without any impairment in tactile sensibilities. Allodynia could only be elicited in SCIP and a significantly higher incidence of pathologically evoked pain (i.e. hyperpathia and wind-up pain) was seen in the chronic pain areas compared to SCINP. We conclude that damage to the spinothalamic tract (STT) is a necessary condition for the occurrence of chronic pain following SCI. However, STT lesion is not a sufficient condition since it could also be found in SCINP. The abnormal evoked pain seen in SCIP is probably due to neuronal hyperexcitability in these subjects. The fact that apparently identical sensory impairments manifest as chronic pain and hyperexcitability in one subject but not in another implies that either genetic predisposition or subtle differences in the nature of spinal injury determine the emergence of chronic pain following SCI.     

Cortical correlates of an attentional bias to painful and innocuous somatic stimuli in children with recurrent abdominal pain

Recurrent abdominal pain (RAP) is a common gastrointestinal problem during childhood. It is not only a pediatric health problem, but may represent a risk factor for chronic pain, psychosomatic symptoms, and psychopathological problems later in life. Alterations in central pain processing and an attentional bias to potentially aversive somatic sensations could contribute to the unfavorable outcome of RAP during childhood. Fourteen children with RAP and 15 control children (age: 10-15 year) participated in an attentional task. Children had to respond to rare targets (tones) and ignore frequent either painful (pain threshold) or non-painful mechanical stimuli delivered at the hand. Event-related cortical potentials in response to the somatic stimuli and the tones were measured and stimulus intensity ratings, reaction time and number of errors were obtained. Painful as compared to non-painful stimuli elicited significantly larger N1, P2 and P3 components of the somatosensory-evoked potential (SEP) in all children. The RAP children responded with a significantly larger P3 to both painful and non-painful stimuli. No group differences were found for the auditory-evoked potentials. Perceived stimulus and pain intensity, reaction time and number of errors did not differ between groups. Similar to findings in adults with functional gastrointestinal disorders (FGIDs), children with RAP did not show somatic hyperalgesia as revealed by unaltered pain thresholds and middle latency pain-evoked SEPs. However, they displayed an attentional bias to painful and non-painful (innocuous) somatic stimuli as indicated by an enhanced P3. This may represent an important mechanism not only for the maintenance of RAP, but also for the development of psychosomatic symptoms.     

Movement imagery increases pain in people with neuropathic pain following complete thoracic spinal cord injury

Spinal cord injury (SCI) results in deafferentation and the onset of neuropathic pain in a substantial proportion of people. Based on evidence suggesting motor cortex activation results in attenuation of neuropathic pain, we sought to determine whether neuropathic SCI pain could be modified by imagined movements of the foot. Fifteen subjects with a complete thoracic SCI (7 with below-level neuropathic pain and 8 without pain) were instructed in the use of movement imagery. Movement imagery was practiced three times daily for 7days. On the eighth day, subjects performed the movement imagery in the laboratory and recorded pain ratings during the period of imagined movement. Six out of 7 subjects with neuropathic pain reported an increase in pain during imagined movements from 2.9+/-0.7 during baseline to 5.0+/-1.0 during movement imagery (p<0.01). In SCI subjects without neuropathic pain, movement imagery evoked an increase in non-painful sensation intensity from a baseline of 1.9+/-0.7 to 4.8+/-1.3 during the movement imagery (p<0.01). Two subjects without a history of pain or non-painful phantom sensations had onset of dysesthesia while performing imagined movements. This study reports exacerbation of pain in response to imagined movements and it contrasts with reports of pain reduction in people with peripheral neuropathic pain. The potential mechanisms underlying this sensory enhancement with movement imagery are discussed.     

Middle short gyrus of the insula implicated in pain processing

Different lines of evidence have suggested an involvement of the insular cortex in pain processing. Direct electrical stimulation (ES) of the human insular cortex during surgical procedure sometimes induces painful sensations and painful stimuli induce activation of the insular cortex as shown by functional neuroimaging. Invasive evaluation of epileptic patients by deep brain stereotactically implanted electrodes provides an opportunity to analyze responses induced by ES of the insular cortex in awake and fully conscious patients. For this study, we included 25 patients suffering from drug refractory focal epilepsy with at least one electrode stereotactically implanted in the insular cortex using an oblique approach (transfrontal or transparietal). Out of the 83 responses induced by insular ES, eight (9.6%) were reported by five patients as painful sensations. Four were restricted to the cephalic region and four were felt on the ipsilateral or bilateral upper limbs, the shoulders and the trunk (pinprick sensations). The eight stimulation sites were anatomically localized via image fusion between pre-implantation 3D MRI and post-implantation 3D CT scans revealing the electrode contacts. All sites inducing painful sensations were restricted to the upper portion of the middle short gyrus of the insula. The findings of this study suggest that middle short gyrus is involved in the processing of pain-producing stimuli.     

Inhibitory effects do not depend on the subjective experience of pain during heterotopic noxious conditioning stimulation (HNCS): a contribution to the psychophysics of pain inhibition.

Heterotopic noxious conditioning stimulation (HNCS) has been thought to give access to the diffuse noxious inhibitory controls (DNIC) in man, which can be activated in wide-dynamic-range neurons by noxious stimulation from remote areas of the body and form the neurophysiological basis of the phenomenon 'pain inhibits pain'. The latter phenomenon suggests that the subjective experience of pain is a prerequisite for an inhibitory action. The necessity of using painful stimuli as conditioning and as test stimuli to produce inhibitory effects was investigated in the present study, using a HNCS paradigm. Twenty young men received conditioning stimuli created by tonic heat at painful and non-painful levels, using either hot water (hand) or thermode (forearm). The test stimuli were phasic heat stimuli (thermode) at painful and non-painful levels applied to the cheek. Only painful but not non-painful heat as conditioning stimulus increased the heat pain threshold and decreased the ability to discriminate between painful heat of different intensities. These two findings are in accord with an inhibitory effect depending on a painful conditioning stimulus. However, the intensity ratings of the test stimuli indicated inhibitory effects of the conditioning stimuli also upon non-painful levels. Furthermore, non-painful heat as conditioning stimulus also appeared to be capable of decreasing the ratings of the test stimuli at painful levels. The latter two findings suggest: (i) that very strong but subjectively still non-painful stimulation can trigger pain inhibitory effects and (ii) that also subjectively non-painful stimuli are affected by inhibitory influences during HNCS.     

Referred sensations in chronic pain patients

This clinical note describes an unusual phenomenon of referred sensation reported in a sample of 98 chronic pain patients during electrical stimulation. Thirty-nine percent reported a variety of sensations referred to different parts of the body. Of these, 74% reported the sensations referred to the painful region. Among the sensations were paresthesias, pain, temperature changes, and pressure or constriction. The patients who had referred sensations had lower ratings of depression and had undergone more surgical operations than those who did not report referred sensations. Three case reports of patients with phantom limb pain are presented to illustrate the vividness with which these sensations are experienced. These data suggest that deafferentation due to disease, injury or other lesions of the CNS lead to a hypersensitivity and an increased likelihood of referred pain of long duration.     

Value of sensory examination in predicting bladder function in patients with T12-L1 fractures and spinal cord injury

OBJECTIVE: To determine whether early sensory examination, voluntary anal sphincter contraction, or bulbocavernosus reflex (BCR) might predict bladder function in patients with a spinal fracture at the thoracolumbar level. DESIGN: Longitudinal study of consecutive patients admitted to a spinal cord injury (SCI) rehabilitation center. SETTING: Primary care center, university facility in Switzerland. PARTICIPANTS: Fifty-five patients with thoracolumbar fractures. INTERVENTIONS: Neurologic (American Spinal Injury Association [ASIA] protocol) and urodynamic examination during the first hospitalization and at follow-up. MAIN OUTCOME MEASURES: Neurologic sensory scores and type of neurogenic bladder. RESULTS: At first examination, there was no correlation between the sensory examination, voluntary anal sphincter contraction, BCR, and neurogenic bladder type. At follow-up (time since first examination: mean, 698+/-47.2d; median, 481d), the sensory examination remained of no value in distinguishing the neurogenic bladder type. However, voluntary anal sphincter contraction distinguished between complete and incomplete neurogenic bladders and BCR differentiated between complete bladder dysfunction of the lower motoneuron and upper motoneuron type. At follow-up, the bladder function (51 patients) remained unchanged in 44 cases and normalized in only 7 cases. Patients who improved their bladder function tended to have higher initial sensory ASIA scores (P<.05, Kruskal-Wallis test). Of the 7 patients who improved their bladder function, all but 1 (85%) had initial perineal pinprick sensation. Nevertheless, preservation of perineal pinprick sensation was of no positive predictive value, because 21 patients (48%) who initially had perineal pinprick sensation did not improve their voiding function, a finding similar to that of the 23 (52%) without initial perineal pinprick sensation whose bladder function also did not improve. CONCLUSIONS: In SCI patients with thoracolumbar fractures, neurogenic voiding dysfunction cannot be predicted by the sensory evaluation. In patients with an SCI at the thoracolumbar level, pinprick sensation in the perineal area is of negative predictive value: absence of pinprick sensation predicts poor bladder recovery. Most patients with a spinal fracture at T12-L1 did not improve in voiding function.     

Lamotrigine in spinal cord injury pain: a randomized controlled trial

The objective was to investigate the effectiveness of lamotrigine for the treatment of spinal cord injury pain and clinical signs of neuronal hyperexcitability. Thirty patients with spinal cord injury (SCI) and at or below level neuropathic pain participated in a randomized double blind, placebo-controlled, crossover trial. A 1-week baseline period was followed by two treatment periods of 9 weeks duration with lamotrigine slowly increased to a maximum of 400 mg or placebo separated by a 2-week washout period. The primary outcome measure was the change in median pain score from baseline week to the last week of treatment. Secondary outcome measures included thresholds to standardized sensory stimuli using quantitative sensory testing. Twenty-two patients completed the trial. We found no statistically significant effect of lamotrigine as evaluated in the total sample. However, in patients with incomplete SCI, lamotrigine significantly reduced pain at or below SCI level. Patients with brush evoked allodynia and wind-up-like pain in the area of maximal pain were more likely to have a positive effect to lamotrigine than patients without these evoked pains (7 of 7 vs. 1 of 14). Lamotrigine was generally well tolerated. While this trial showed no significant effect on spontaneous and evoked pain in complete and incomplete spinal cord injury, lamotrigine reduced spontaneous pain in patients with incomplete spinal cord injury and evoked pain in the area of spontaneous pain.     

Tactual sensitivity of chronic pain patients to non-painful stimuli

Chronic pain research tends to focus on responses to thresholds, tolerance, and discrimination involving painful stimuli. This investigation, however, examines responses of individuals with chronic pain to non-painful stimuli. Two-point thresholds were obtained from 19 chronic pain patients and 17 pain-free individuals. The chronic pain patients had a significantly higher two-point threshold, 40.3 mm (S.D., 15.0 mm) than that of the control group, which had a two-point threshold of 30.8 mm (S.D., 7.4 mm). The results indicate that chronic pain decreases tactual sensitivity to non-painful stimuli.     

Function-limiting dysesthetic pain syndrome among traumatic spinal cord injury patients: a cross-sectional study

Diffuse burning dysesthetic sensations distal to the level of spinal injury are the most common and disabling painful sequelae of traumatic spinal cord injury (SCI). In a cross-sectional study of 19 SCI patients, clinical characteristics and results of 3 validated pain measurement instruments (McGill Pain Questionnaire, Sternbach Pain Intensity and Zung Pain and Distress Scale) were used to develop a profile of function-limiting dysesthetic pain syndrome (DPS). Compared to a cohort of 147 patients admitted to the Midwest Regional Spinal Cord Injury Care System during the time period of the study, subjects were more likely to have paraplegia, incomplete sensory myelopathy, gunshot wounds to the spine and non-surgical spinal stabilization. Most patients described the pain as 'cutting,' 'burning,' 'piercing,' 'radiating' and 'tight.' The majority of patients located the pain internally and in the lower extremities. Values obtained from 6 McGill Pain Questionnaire subscales, 2 Sternbach Pain Intensity ratings and the Zung Pain and Distress index equalled or exceeded those reported for other pain syndromes. Use of these validated pain measures resulted in a systematic comprehensive assessment of function-limiting DPS following SCI.     

Induction of non-painful and painful intestinal sensations by hypertonic saline: a new human experimental model.

BACKGROUND AND AIMS: To develop a pain model for chemical stimulation of the human gut. METHODS: In a double-blind experimental study 10 subjects with a previously performed sigmoidostomy were randomised to receive injections with either isotonic or hypertonic saline in the colonic mucosa. In the hypertonic experimental arm, 0.1 ml of 0.9%, 2%, 4%, and 6% and 0.2 ml of 2% and 4% saline were given. In the placebo arm, six 0.9% saline injections of the same quantities were given. In a separate experiment 0.8 ml 4% saline was infused into the mucosa by a pump over a period of 2min. The pain intensity was rated on a 0-10 visual analogue scale with 5 as the pain threshold. RESULTS: The hypertonic saline injections resulted in local as well as referred non-painful and painful sensations in 9 out of the 10 subjects. The evoked sensations were mostly described as a smarting sensation with an intensity of median 1 (range 0-5.6) for 0.1 ml 2% saline to median 2.9 (range 0-6.2) for 0.2 ml 4% saline. Seven subjects reported referred sensations to the abdominal skin. Continuous infusion of 4% saline resulted in a consistent sensory response in all subjects, with a median intensity of 4.1 (range 2.1-8.1). This sensory intensity was reproducible in 70% in a retest experiment after median 7 weeks. In the placebo arm a total of 70 isotonic saline injections only resulted in inconsistent, short-lasting non-painful sensations in three subjects. CONCLUSION: The model represents a safe method for direct chemical activation of the sensory endings in the human gut. The model may be used for pharmacological screening of analgesics and for basic investigations in patients suffering from gastrointestinal diseases.     

Somatosensory event-related potentials to painful and non-painful stimuli: effects of attention

In order to determine the effects of attention and distraction on painful and non-painful stimuli, the amplitude changes of 3 components (N150, P200, P300) of the somatosensory event-related potential (SERP) elicited by painful and non-painful electrical stimuli were investigated. Painful and non-painful stimuli were determined using a visual analog scale. SERPs were recorded from 16 healthy volunteers at 5 midline and 4 left and 4 right hemispheric sites. The differences between the amplitudes of attended and ignored stimuli were quantified with a baseline-to-peak measure. ANOVA results revealed no significant attention or stimulus intensity effects for N150 but highly significant differences in P200 and P300 amplitudes between attended and ignored stimuli. In addition, P200 and P300 amplitudes were larger for strong stimuli than for weak stimuli, with no significant differences between non-painful and painful stimuli. These findings are consistent with the existence of a relative, rather than an absolute, relationship between SERP component amplitudes and subjective pain reports. Furthermore, the data give evidence that attentional manipulations represent a powerful method to decrease the perception of pain and that, when used with subjective and behavioral measures, the SERP represents a valuable asset in the multidimensional approach to pain measurement and assessment.     

Pain in patients with spinal cord injury

For this study of intractable pain after spinal cord injury (SCI), a questionnaire was developed, pilot-tested and mailed to 356 previously hospitalized SCI patients, 200 (56%) of whom returned the completed questionnaire. Of the respondents, 160 (80%) reported abnormal sensation and 96 (48%) called the discomfort painful. Abnormal sensations were first noted within 6 months of injury by 105 patients, from 7 months to 4 years after injury by 39, and longer than 4 years after injury or unknown by 16. Pain locations varied and were unrelated to the level of lesion. In 30% of those reporting abnormal sensation the location of pain remained stationary, whereas in 17% it changed over time. The intensity of pain was described as severe to extreme by 25%; 44% indicated that it interfered with daily activities. Increase of pain over time was noted by 41%. Activity, inactivity, weather change and overexertion were not frequently identified as aggravating circumstances. Rest and medication were cited as alleviating factors. Approximately 38% of those experiencing pain used medications but only 22% obtained consistent relief from their use. Patients with low level lesions were more willing to exchange a hypothetical chance of recovery and/or loss of reacquired physiologic functions for pain relief than were patients with higher lesions.     

Delayed cervical spinal cord injury after high voltage electrical injury: a case report.

High voltage electrical injuries usually cause devastating consequences for patients, most of which result in permanent disability. Spinal cord injury (SCI) caused by high voltage electrical injury is uncommon in the literature. We present a 29-year-old male patient who was diagnosed as having delayed SCI after high voltage electrical injury. The patient developed muscle weakness in the lower extremities with the loss of pinprick sensation below the fifth cervical spinal segment, 2 days after the high voltage electrical injury. Magnetic resonance imaging of the brain, cervical and thoracic spine was normal. Nerve conduction and needle electromyography studies were normal, except for bilateral tibial and left median somatosensory-evoked potentials. The findings on initial examination and neurophysical investigation showed incomplete cervical SCI at the C5 level. He was able to walk with a pair of canes and bilateral ankle-foot orthosis at the end of the 2-month rehabilitation. Follow-up physical and electrophysiological examination of the patient 15 months after injury showed further improvement. The patient was able to walk with a pair of canes without orthoses. Electrophysiological studies are useful instruments in the diagnosis and follow-up of these patients. Early rehabilitation is essential to obtain a favorable outcome in patients with SCI caused by high voltage electrical injury.     

Sensory dissociation in chronic low back pain: Two case reports

Patients with chronic low back pain often report that they do not perceive their painful back accurately. Previous studies confirmed that sensory dissociation and/or discrepancy between perceived body image and actual size is one of the specific traits of patients with chronic pain. Current approaches for measuring sensory dissociation are limited to two-point-discrimination or rely on pain drawings not allowing for quantitative analysis. This case study reports the sensory dissociation of two cases with chronic low back pain using a recently published test (point-to-point-test (PTP)) and a newly developed test (two-point-estimation (TPE)). Both patients mislocalized tactile stimuli delivered to the painful location compared to non-painful locations (PTP test). In addition, both patients perceived their painful lumbar region differently from non-painful sites above and below and contralateral to the painful site. TPE data showed two distinct clinical patterns of sensory dissociation: one patient perceived the two-point distance in the painful area as expanded, while the other patient perceived it as shrunk. The latter pattern of sensory dissociation (i.e., pattern shrunk) is likely to respond to sensory training. Whether enlarged patterns of sensory dissociation are more resistant to treatment remains unknown but would explain the low effectiveness of previous studies using sensory training in chronic low back pain populations. Subgrouping patients according to their sensory discrimination pattern could contribute to the choice and effectiveness of the treatment approach.     

Functional Characterization of At-Level Hypersensitivity in Patients With Spinal Cord Injury

At-level and above-level hypersensitivity was assessed in patients with chronic complete thoracic spinal cord injury (SCI). Patients were classified using somatosensory mapping (brush, cold, pinprick) and assigned into 2 groups (ie, patients with at-level hypersensitivity [SCIHs, n = 8] and without at-level hypersensitivity [SCINHs, n = 7]). Gender and age-matched healthy subjects served as controls. Quantitative sensory testing (QST), electrically- and histamine-induced pain and itch, laser Doppler imaging, and laser-evoked potentials (LEP) were recorded at-level and above-level in SCI-patients. Six of 8 SCIHs, but 0 of 7 SCINHs patients suffered from neuropathic below-level pain. Clinical sensory mapping revealed spreading of hypersensitivity to more cranial areas (above-level) in 3 SCIHs. Cold pain threshold measures confirmed clinical hypersensitivity at-level in SCIHs. At-level and above-level hypersensitivity to electrical stimulation did not differ significantly between SCIHs and SCINHs. Mechanical allodynia, cold, and pin-prick hypersensitivity did not relate to impaired sensory function (QST), axon reflex flare, or LEPs. Clinically assessed at-level hypersensitivity was linked to below-level neuropathic pain, suggesting neuronal hyperexcitability contributes to the development of neuropathic pain. However, electrically evoked pain was not significantly different between SCI patients. Thus, SCI-induced enhanced excitability of nociceptive processing does not necessarily lead to neuropathic pain. QST and LEP revealed no crucial role of deafferentation for hypersensitivity development after SCI.

Phantom phenomena in mastectomized patients and their relation to chronic and acute pre-mastectomy pain

Chronic and acute pre-mastectomy pain as well as prevalence and characteristics of phantom phenomena following mastectomy were investigated by interview in a sample of 39 women who had undergone unilateral breast amputation. Twenty of 39 participants reported phantom sensations in the breast. Nine of the participants with phantom sensations experienced phantom pain and 11 non-painful phantom sensations. Although some features of phantom breast phenomena appear to be similar to characteristics of phantom phenomena in limb amputees, phantom breast phenomena seem to differ in a variety of ways such as time of onset or localization. This difference may be explained by the absence of kinesthesis and the small representation of the human breast. Seven of the 39 participants experienced chronic and six acute breast pain prior to the amputation. The amount of chronic pre-mastectomy breast pain weighted by the amount of involved tissue was significantly higher among participants with non-painful phantom sensations, compared to women with painful phantoms and those without phantom phenomena.     

Neuroelectric source imaging of steady-state movement-related cortical potentials in human upper extremity amputees with and without phantom limb pain

Whereas several studies reported a close relationship between changes in the somatotopic organization of primary somatosensory cortex and phantom limb pain, the relationship between alterations in the motor cortex and amputation-related phenomena has not yet been explored in detail. This study used steady-state movement-related cortical potentials (MRCPs) combined with neuroelectric source imaging to assess the relationship of changes in motor cortex and amputation-related phenomena such as painful and non-painful phantom and residual limb sensations, telescoping, and prosthesis use. Eight upper limb amputees were investigated. A significant positive relationship between reorganization of the motor cortex (distance of the MRCP source location from the mirrored source for hand movement) and phantom limb pain was found. Non-painful phantom sensations as well as painful and non-painful residual limb sensations were unrelated to motor cortical reorganization. A higher amount of motor reorganization was associated with less daily prosthesis use, which also tended to be related to more severe phantom limb pain. These results extend previous findings of a positive relationship between somatosensory reorganization and phantom limb pain to the motor domain and suggest a potential positive effect of prosthesis use on phantom limb pain and cortical reorganization.     

Relationships between near surface blood flow and altered sensations among spinal cord injured veterans

Ten patients with clinical diagnoses of complete transverse spinal cord tissue destruction were interviewed about any sensations they felt below the level at which normal feelings were evident. All ten reported experiencing various feelings most of the time and nine reported that some of those feelings were usually quite painful. Videothermographs showing differences in skin temperature of 0.1 degrees celsius were taken to evaluate blood flow patterns to a depth of 1.5 cm. Changes in blood flow patterns were found to correlate highly with the level at which sensations changed from normal to abnormal and to correlate virtually exactly with the locations of pain reported from supposedly desenate areas.     

Pharmacological dissection of the paradoxical pain induced by a thermal grill

We investigated the role of the glutamatergic and endogenous opioidergic systems in the paradoxical pain evoked by the simultaneous application of innocuous warm and cold stimuli to the skin with a "thermal grill". Two parallel randomized, double-blind, cross-over studies, including two groups of 12 healthy volunteers, were carried out to compare the effects of i.v. ketamine or naloxone to those of placebo, on the sensations produced by a thermode (i.e. thermal grill) composed of six bars applied on the palmar surface of the right hand. The temperature of alternate (even- and odd-numbered) bars could be controlled independently by Peltier elements to produce various patterns of the grill. During each experimental session we measured the effects of ketamine, naloxone or placebo on the intensity of: (i) paradoxical pain; (ii) "normal" thermal (heat and cold) pain; and (iii) non-painful thermal (warm and cool) sensations. Ketamine administration resulted in a significant reduction of paradoxical pain intensity but did not alter normal pain or non-painful thermal sensations. By contrast, naloxone had no effect on paradoxical pain, normal pain or non-painful thermal sensations. This study demonstrates for the first time that the "thermal grill illusion of pain" can be modulated pharmacologically. This paradoxical pain, which involves the glutamatergic systems, acting through the NMDA receptors, but not the tonic endogenous opioids systems, might share some mechanisms with pathological pain.