Psychologically based interventions for adults with chronic neuropathic pain: a scoping review.

OBJECTIVE: As psychologically based interventions have been shown to have clinical utility for adults with chronic pain generally, a similar benefit might be expected in the management of chronic neuropathic pain (NeuP). However, to date, this has not been established, with existing systematic reviews on this topic being hampered by the scarcity of randomized controlled trials (RCTs). This review aimed to identify the type of psychologically based interventions studied for adults with chronic NeuP. It also aimed to assess whether there are enough RCTs to justify undertaking an updated systematic review. METHODS: Seven databases and 2 clinical trial registries were searched for NeuP and psychologically based interventions from database inception to December 2021, and the search was updated in February 2023. The search was broadened by reviewing the reference list of included studies and contacting field experts. Predetermined study characteristics were extracted. RESULTS: Of 4682 records screened, 33 articles (less than 1%) met the eligibility criteria. Four broad intervention approaches were observed, including cognitive-behavioral approaches (n = 16), mindfulness/meditation (n = 10), trauma-focused therapy (n = 4), and hypnosis (n = 3). Thirteen RCTs were identified, and of these, 9 retained 20 participants in each arm after treatment. CONCLUSIONS: Cognitive-behavioral therapy was the most common therapeutic approach identified, whereas mindfulness/meditation was the most frequently used technique. Almost half to two-thirds of the studies reported significant improvements in pain, disability, or distress, which suggests that psychologically based interventions are potentially beneficial for adults with chronic NeuP. An updated systematic review seems warranted. STUDY REGISTRATION: Open Science Framework (https://osf.io) (December 6, 2021; DOI: 10.17605/OSF.IO/WNSTM).

A Systematic Review of the Variation in Pain Catastrophizing Scale Reference Scores Based on Language Version and Country in Patients with Chronic Primary (Non-specific) Pain.

INTRODUCTION: This systematic review aimed to investigate variations of reference scores for the Pain Catastrophizing Scale (PCS) between language versions and between countries in patients with chronic primary pain (CPP) or chronic primary pain, not otherwise specified (CPP-NOS). METHODS: Electronic searches of the Ovid/Embase, Ovid/MEDLINE, and Ovid/PsycINFO databases were conducted to retrieve studies assessing PCS scores in adults with CPP or CPP-NOS proposed by the International Classification of Diseases, Eleventh Revision for any country where the translated PCS was available. The protocol for this systematic review was prospectively registered on the International Prospective Register of Systematic Reviews 2018 (registration number: CRD 42018086719). RESULTS: A total of 3634 articles were screened after removal of duplicates. From these, 241 articles reporting on 32,282 patients with chronic pain were included in the review. The mean (± standard deviation) weighted PCS score across all articles was 25.04 ± 12.87. Of the 12 language versions and 21 countries included in the review, the weighted mean PCS score in Asian languages or Asian countries was significantly higher than that in English, European, and other languages or Western and other countries. The highest mean score of the weighted PCS based on language was in Japanese (mean 33.55), and the lowest was in Russian (mean 20.32). The highest mean score of the weighted PCS based on country was from Japan (mean 33.55), and the lowest was from Australia (mean 19.80). CONCLUSION: The weighted PCS scores for people with CPP or CPP-NOS were significantly higher in Asian language versions/Asian countries than in English, European and other language versions or Western and other countries.

Our previous research has indicated that the clinical significance of the Pain Catastrophizing Scale (PCS) score would vary across different language versions and different countries (Ikemoto et al. in Eur J Pain 2020; 24(7):1228­1241. https://doi.org/10.1002/ejp.1587 ). This systematic review investigated cross-cultural differences in the PCS score between different languages and countries among patients with chronic primary pain. From 241 articles reporting on 32,282 patients with chronic primary pain, involving 12 language versions and 21 countries, the weighted mean PCS score in Asian languages or Asian countries was significantly higher than that in English, European and other languages or Western and other countries. Given the variations of PCS scores in different contexts, a universal comparison PCS reference or a cutoff score should not be used to compare different cultures even when a sample has the same pain condition.

An Exploratory EEG Analysis on the Effects of Virtual Reality in People with Neuropathic Pain Following Spinal Cord Injury.

Neuropathic pain in people with spinal cord injury is thought to be due to altered central neuronal activity. A novel therapeutic intervention using virtual reality (VR) head-mounted devices was investigated in this study for pain relief. Given the potential links to neuronal activity, the aim of the current study was to determine whether use of VR was associated with corresponding changes in electroencephalography (EEG) patterns linked to the presence of neuropathic pain. Using a within-subject, randomised cross-over pilot trial, we compared EEG activity for three conditions: no task eyes open state, 2D screen task and 3D VR task. We found an increase in delta activity in frontal regions for 3D VR with a decrease in theta activity. There was also a consistent decrease in relative alpha band (8-12 Hz) and an increase in low gamma (30-45 Hz) power during 2D screen and 3D VR corresponding, with reduced self-reported pain. Using the nonlinear and non-oscillatory method of extracting fractal dimensions, we found increases in brain complexity during 2D screen and 3D VR. We successfully classified the 3D VR condition from 2D screen and eyes opened no task conditions with an overall accuracy of 80.3%. The findings in this study have implications for using VR applications as a therapeutic intervention for neuropathic pain in people with spinal cord injury.

The short-term effects of head-mounted virtual-reality on neuropathic pain intensity in people with spinal cord injury pain: a randomised cross-over pilot study.

STUDY DESIGN: Within-subject, randomised cross-over trial. OBJECTIVES: To determine whether a commercially available 3D head-mounted (HMD) virtual reality (VR) device results in significant reductions in neuropathic pain compared to using a 2D screen device in people with spinal cord injury (SCI). SETTING: Greenwich Hospital, Sydney, Australia. METHODS: Sixteen men with established SCI and chronic neuropathic pain participated in a single-session randomised cross-over trial. We compared the effects of 3D HMD VR and a 2D screen application on SCI neuropathic pain intensity and levels of perceived presence. RESULTS: Participants reported significantly lower pain intensity after 3D HMD VR compared to 2D screen application (1.9 ± SD 1.8 versus 3.4 ± SD 1.6, mean 95% CI: 1.5, P < 0.0001). Participants reported significantly higher perceived levels of presence with the 3D HMD VR compared to 2D screen of (49.6 ± SD 8.9 versus 32.8 ± SD 11.1, mean 95% CI: 16.6, P < 0.0001). Increased perceived presence was associated with significantly lower pain intensity regardless of randomised sequencing of the two conditions (mean 95% CI: 0.06, P = 0.005). Effect size for pain reduction using 3D HMD VR was 0.80. CONCLUSIONS: We suggest that 3D HMD VR may provide neuropathic pain relief for people with SCI. Given the lack of cybersickness and ease of access, we propose that immersive VR could be a helpful adjunct to current pharmacotherapy. Further research is required to show that VR can be effective for more long-term reductions in SCI pain.

Reducing the use of opioids by patients with chronic pain: an effectiveness study with long-term follow-up.

This study addresses the problem of long-term opioid use by chronic pain patients. The study involved a secondary analysis of unanalyzed data from a published study of 2 versions of cognitive-behavioural therapy-based interdisciplinary treatment for chronic pain. In this study, we examined whether the use of opioids by 140 chronic pain patients could be ceased sustainably over 12 months after participation in the comprehensive interdisciplinary pain management program aimed at enhancing pain self-management. On admission to the treatment, there were no significant differences between those patients taking or not taking opioids on usual pain, pain interference in daily activities, pain-related disability, depression severity, as well as in pain cognitions. After the treatment, the use of opioids was significantly reduced, both in numbers taking any and in mean doses, and these gains were maintained over the 12-month follow-up. Finally, cessation of opioids during treatment was associated with more substantial and consistent improvements in usual pain, depression severity, pain interference, pain-related disability, and pain cognitions, relative to those who reduced their opioids but did not cease them. These findings support the idea of using training in pain self-management strategies as a viable alternative to long-term opioid use by patients with chronic pain.

Conditioned Pain Modulation (CPM) is Reduced in Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of CPM and the Role of Psychological Factors.

This systematic review summarises evidence assessing endogenous pain inhibition in people with irritable bowel syndrome (IBS) compared with healthy controls using conditioned pain modulation (CPM) and offset analgesia (OA). Evidence regarding the role of psychological variables is also examined. The review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Four electronic databases were searched to retrieve studies assessing CPM or OA in adults diagnosed with IBS according to the ROME II/III criteria. Standardized mean differences were calculated for each study and a random effects model was used for meta-analysis. Eleven studies were included, 5 of which reported results on the relationship between CPM and psychological variables. None of the studies assessed OA. The risk of bias assessment found a lack of assessor blinding in all studies. The pooled effect estimate was 0.90 (95% CI, 0.40-1.40) indicating a significantly lower CPM effect in people with IBS compared with controls. This effect was reduced to 0.51 when 1 outlier was excluded from the analysis. In addition, reduced CPM responses were significantly correlated with higher anxiety (r=0.17 to 0.64), stress (r=0.63), and pain catastrophizing (r=0.38) in people with IBS; however, the evidence available was limited and the strength of these associations variable. Depression was not found to be associated with CPM in these IBS cohorts. The results of this review suggest that people with IBS, as a group, demonstrate reduced pain inhibition measured by CPM. The preliminary evidence about the association between psychological factors and CPM warrants further investigations.

Vibration testing: Optimizing methods to improve reliability.

INTRODUCTION: In this study we assessed the test-retest reliability of a Rydel-Seiffer tuning fork and an electronic vibrameter with hand-held and fixed probes. METHODS: Fifty healthy volunteers were assessed twice in the upper and lower limb 15 minutes apart. Reliability was assessed by intraclass correlation coefficient (ICC) and standard error of measurement (SEM). The effect of stimulus parameters on vibration disappearance threshold (VDT) was assessed by analysis of variance. RESULTS: All 3 tools showed good reliability (ICCs = 0.65-0.95). Vibrameter recordings with the fixed probe showed high variability. The vibrameter was more sensitive in detecting body-site and age differences in vibration thresholds than the tuning fork. Significantly higher VDT was observed when higher starting amplitudes and slower rates of change were used. DISCUSSION: The hand-held vibrameter is a superior tool to monitor vibration sense. The stimulus amplitude and rate of change are important to control as they alter VDT. Muscle Nerve 59:229-235, 2019.

From acute to persistent low back pain: a longitudinal investigation of somatosensory changes using quantitative sensory testing-an exploratory study.

INTRODUCTION: Chronic low back pain (LBP) is commonly associated with generalised pain hypersensitivity. It is suggested that such somatosensory alterations are important determinants for the transition to persistent pain from an acute episode of LBP. Although cross-sectional research investigating somatosensory function in the acute stage is developing, no longitudinal studies designed to evaluate temporal changes have been published. OBJECTIVES: This exploratory study aimed to investigate the temporal development of somatosensory changes from the acute stage of LBP to up to 4 months from onset. METHODS: Twenty-five people with acute LBP (<3 weeks' duration) and 48 pain-free controls were prospectively assessed at baseline using quantitative sensory testing with the assessor blinded to group allocation, and again at 2 and 4 months. Psychological variables were concurrently assessed. People with acute LBP were classified based on their average pain severity over the previous week at 4 months as recovered (≤1/10 numeric rating scale) or persistent (≥2/10 numeric rating scale) LBP. RESULTS: In the persistent LBP group, (1) there was a significant decrease in pressure pain threshold between 2 and 4 months (P < 0.013), and at 4 months, pressure pain threshold was significantly different from the recovered LBP group (P < 0.001); (2) a trend towards increased temporal summation was found at 2 months and 4 months, at which point it exceeded 2 SDs beyond the pain-free control reference value. Pain-related psychological variables were significantly higher in those with persistent LBP compared with the recovered LBP group at all time points (P < 0.05). CONCLUSION: Changes in mechanical pain sensitivity occurring in the subacute stage warrant further longitudinal evaluation to better understand the role of somatosensory changes in the development of persistent LBP. Pain-related cognitions at baseline distinguished persistent from the recovered LBP groups, emphasizing the importance of concurrent evaluation of psychological contributors in acute LBP.

New evidence for preserved somatosensory pathways in complete spinal cord injury: A fMRI study.

Trauma to the spinal cord rarely results in complete division of the cord with surviving nerves sometimes remaining silent or failing to function normally. The term motor or sensory discomplete has been used to describe this important but unclassified subgroup of complete SCI. Importantly, silent motor or sensory pathways may contribute to aversive symptoms (spasticity, pain) or improved treatment success. To demonstrate more objectively the presence of subclinical preserved somatosensory pathways in clinically complete SCI, a cross-sectional study using functional MRI (fMRI) was undertaken. The presence of brain activation following innocuous brushing of an insensate region below-injury (great toe) was analyzed in 23 people (19 males (83%), mean ± SD age 43 ± 13 years) with clinically complete (AIS A) SCI with (n = 13) and without (n = 10) below-level neuropathic pain and 21 people without SCI or pain (15 males (71%); mean ± SD age 41 ± 14 years). Location appropriate, significant fMRI brain activation was detected in 48% (n = 11/23) of subjects with clinically complete SCI from below-injury stimulation. No association was found between the presence of subclinical sensory pathways transmitting innocuous mechanical stimuli (dorsal column medical lemniscal) and below-level neuropathic pain (χ2  = 0.034, P = 0.9). The high prevalence of sensory discomplete injuries (∼50% complete SCI) strengthens the case to explore inclusion of this category into the international SCI taxonomy (ISNCSCI). This would ensure more widespread inclusion of discomplete SCI in ongoing pain and motor recovery research. Neurophysiological tests such as fMRI may play a role in this process. Hum Brain Mapp 39:588-598, 2018. © 2017 Wiley Periodicals, Inc.

The long-term reliability of static and dynamic quantitative sensory testing in healthy individuals.

Quantitative sensory tests (QSTs) have been increasingly used to investigate alterations in somatosensory function in a wide range of painful conditions. The interpretation of these findings is based on the assumption that the measures are stable and reproducible. To date, reliability of QST has been investigated for short test-retest intervals. The aim of this study was to investigate the long-term reliability of a multimodal QST assessment in healthy people, with testing conducted on 3 occasions over 4 months. Forty-two healthy people were enrolled in the study. Static and dynamic tests were performed, including cold and heat pain threshold (CPT, HPT), mechanical wind-up [wind-up ratio (WUR)], pressure pain threshold (PPT), 2-point discrimination (TPD), and conditioned pain modulation (CPM). Systematic bias, relative reliability and agreement were analysed using repeated measure analysis of variance, intraclass correlation coefficients (ICCs3,1) and SE of the measurement (SEM), respectively. Static QST (CPT, HPT, PPT, and TPD) showed good-to-excellent reliability (ICCs: 0.68-0.90). Dynamic QST (WUR and CPM) showed poor-to-good reliability (ICCs: 0.35-0.61). A significant linear decrease over time was observed for mechanical QST at the back (PPT and TPD) and for CPM (P < 0.01). Static QST were stable over a period of 4 months; however, a small systematic decrease over time has been observed for mechanical QST. Dynamic QST showed considerable variability over time; in particular, CPM using PPT as the test stimulus did not show adequate reliability, suggesting that this test paradigm may be less useful for monitoring individuals over time.

Prognostic value of quantitative sensory testing in low back pain: a systematic review of the literature.

Quantitative sensory testing (QST) measures have recently been shown to predict outcomes in various musculoskeletal and pain conditions. The aim of this systematic review was to summarize the emerging body of evidence investigating the prognostic value of QST measures in people with low back pain (LBP). The protocol for this review was prospectively registered on the International Prospective Register of Systematic Reviews. An electronic search of six databases was conducted from inception to October 2015. Experts in the field were contacted to retrieve additional unpublished data. Studies were included if they were prospective longitudinal in design, assessed at least one QST measure in people with LBP, assessed LBP status at follow-up, and reported the association of QST data with LBP status at follow-up. Statistical pooling of results was not possible due to heterogeneity between studies. Of 6,408 references screened after duplicates removed, three studies were finally included. None of them reported a significant association between the QST measures assessed and the LBP outcome. Three areas at high risk of bias were identified which potentially compromise the validity of these results. Due to the paucity of available studies and the methodological shortcomings identified, it remains unknown whether QST measures are predictive of outcome in LBP.

Descending pain modulation in irritable bowel syndrome (IBS): a systematic review and meta-analysis.

BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder. While abdominal pain is a dominant symptom of IBS, many sufferers also report widespread hypersensitivity and present with other chronic pain conditions. The presence of widespread hypersensitivity and extra-intestinal pain conditions suggests central nervous dysfunction. While central nervous system dysfunction may involve the spinal cord (central sensitisation) and brain, this review will focus on one brain mechanism, descending pain modulation. METHOD/DESIGN: We will conduct a comprehensive search for the articles indexed in the databases Ovid MEDLINE, Ovid Embase, Ovid PsycINFO and Cochrane Central Register of Controlled Trial (CENTRAL) from their inception to August 2015, that report on any aspect of descending pain modulation in irritable bowel syndrome. Two independent reviewers will screen studies for eligibility, assess risk of bias and extract relevant data. Results will be tabulated and, if possible, a meta-analysis will be carried out. DISCUSSION: The systematic review outlined in this protocol aims to summarise current knowledge regarding descending pain modulation in IBS. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015024284.

Thermal quantitative sensory testing: a study of 101 control subjects.

Quantitative sensory testing is useful for the diagnosis, confirmation and monitoring of small fibre neuropathies. Normative data have been reported but differences in methodology, lack of age-specific values and graphical presentation of data make much of these data difficult to apply in a clinical setting. We have collected normative age-specific thermal threshold data for use in a clinical setting and clarified other factors influencing reference values, including the individual machine or operator. Thermal threshold studies were performed on 101 healthy volunteers (21-70 years old) using one of two Medoc Thermal Sensory Analyser II machines (Medoc, Ramat Yishai, Israel) with a number of operators. A further study was performed on 10 healthy volunteers using both machines and one operator at least 3 weeks apart. Thermal threshold detection increases with age and is different for different body regions. There is no significant difference seen in results between machines of the same make and model; however, different operators may influence results. Normative data for thermal thresholds should be applied using only age- and region-specific values and all operators should be trained and strictly adhere to standard protocols. To our knowledge, this is the largest published collection of normal controls for thermal threshold testing presented with regression data which can easily be used in the clinical setting.

Early changes in somatosensory function in spinal pain: a systematic review and meta-analysis.

Alterations in sensory processing have been demonstrated in chronic low back and neck pain. However, it has not been yet systematically summarized how early these changes occur in spinal pain. This systematic review examines the available literature measuring somatosensory function in acute (<6 weeks) and subacute (6-12 weeks) spinal pain. The protocol for this review has been registered on the International Prospective Register of Systematic Reviews (PROSPERO). An electronic search of 4 databases was conducted to retrieve studies assessing somatosensory function by quantitative sensory testing in adults with spinal pain of up to 12 weeks duration. Two reviewers independently screened the studies and assessed the risk of bias. Studies were grouped according to spinal pain condition (whiplash injury, idiopathic neck pain, and nonspecific low back pain), and, where possible, meta-analyses were performed for comparable results. Fifteen studies were included. Sources of bias included lack of assessor blinding, unclear sampling methods, and lack of control for confounders. We found that: (1) there is consistent evidence for thermal and widespread mechanical pain hypersensitivity in the acute stage of whiplash, (2) there is no evidence for pain hypersensitivity in the acute and subacute stage of idiopathic neck pain, although the body of evidence is small, and (3) hyperalgesia and spinal cord hyperexcitability have been detected in early stages of nonspecific low back pain, although evidence about widespread effects are conflicting. Future longitudinal research using multiple sensory modalities and standardized testing may reveal the involvement of somatosensory changes in the development and maintenance of chronic pain.

Longstanding neuropathic pain after spinal cord injury is refractory to transcranial direct current stimulation: a randomized controlled trial.

Neuropathic pain remains one of the most difficult consequences of spinal cord injury (SCI) to manage. It is a major cause of suffering and adds to the physical, emotional, and societal impact of the injury. Despite the use of the best available treatments, two thirds of people experiencing neuropathic pain after SCI do not achieve satisfactory pain relief. This study was undertaken in response to a recent clinical trial reporting short-term, clinically significant reductions in neuropathic SCI pain with primary motor cortex transcranial direct current stimulation (tDCS). In this investigation, we aimed to build on this previous clinical trial by extending the assessment period to determine the short-, medium-, and long-term efficacy of tDCS for the treatment of neuropathic pain after SCI. We found that, contrary to previous reports, after 5 tDCS treatment periods, mean pain intensity and unpleasantness rating were not significantly different from initial assessment. That is, in this trial tDCS did not provide any pain relief in subjects with neuropathic SCI pain (n=10). A similar lack of effect was also seen after sham treatment. Because the injury duration in this study was significantly greater than that of previous investigations, it is possible that tDCS is an effective analgesic only in individuals with relatively recent injuries and pain. Future investigations comparing a range of injury durations are required if we are to determine whether this is indeed the case.

The effects of a single mild dose of morphine on chemoreflexes and breathing in obstructive sleep apnea.

The effect of morphine on breathing and ventilatory chemoreflexes in obstructive sleep apnea (OSA) is unknown. It has been assumed that acute morphine use may induce deeper respiratory depression in OSA but this has not been investigated. We evaluated awake ventilatory chemoreflexes and overnight polysomnography on 10 mild-moderate OSA patients before and after giving 30 mg oral controlled-release morphine. Morphine plasma concentrations were analysed. We found a 30-fold range of morphine plasma concentrations with the fixed dose of morphine, and a higher plasma morphine concentration was associated with a higher CO(2) recruitment threshold (VRT) (r=0.86, p=0.006) and an improvement in sleep time with Sp(O(2)) (T90) (r=-0.87, p=0.005) compared to the baseline. The improvement in T90 also significantly correlated with the increase of VRT (r=-0.79, r=0.02). In conclusion, in mild-to-moderate OSA patients, a single common dose of oral morphine may paradoxically improve OSA through modulating chemoreflexes. There is a large inter-individual variability in the responses, which may relate to individual morphine metabolism.

Functional reorganization of the brain in humans following spinal cord injury: evidence for underlying changes in cortical anatomy.

Loss of somatosensory drive results in functional reorganization of the primary somatosensory cortex (SI). While the phenomenon of functional cortical reorganization is well established, it remains unknown whether in humans, functional reorganization results from changes in brain anatomy, or simply reflects an unmasking of already existing dormant synapses. In 20 subjects with complete thoracic spinal cord injuries (SCIs) and 23 controls, we used functional and structural magnetic resonance imaging to determine whether SI reorganization was associated with changes in SI anatomy. SCI resulted in a significant SI reorganization, with the little finger representation moving medially toward the lower body representation (i.e., area of sensory loss). Furthermore, although SCI was associated with gray matter volume loss in the lower body representation, this loss was minimized as reorganization increased. That is, the greater the medial shift in little finger representation, the greater the gray matter preservation in the lower body representation. In addition, in the region of greatest SI reorganization (little finger), fractional anisotropy was correlated with SI reorganization. That is, as SI reorganization increased, the extent of aligned structures decreased. Finally, although thalamocortical fibers remained unchanged, the ease and direction of water movement within the little finger representation was altered, being directed more toward the midline in SCI subjects. These data show that SI reorganization following SCI is associated with changes in SI anatomy and provide compelling evidence that SI reorganization in humans results from the growth of new lateral connections, and not simply from the unmasking of already existing lateral connections.

Dissociation of µ- and δ-opioid inhibition of glutamatergic synaptic transmission in superficial dorsal horn.

BACKGROUND: There is anatomical and behavioural evidence that µ- and δ-opioid receptors modulate distinct nociceptive modalities within the superficial dorsal horn. The aim of the present study was to examine whether µ- and δ-opioid receptor activation differentially modulates TRP sensitive inputs to neurons within the superficial dorsal horn. To do this, whole cell patch clamp recordings were made from lamina I - II neurons in rat spinal cord slices in vitro to examine the effect of opioids on TRP agonist-enhanced glutamatergic spontaneous miniature excitatory postsynaptic currents (EPSCs). RESULTS: Under basal conditions the µ-opioid agonist DAMGO (3 µM) reduced the rate of miniature EPSCs in 68% of neurons, while the δ- and κ-opioid agonists deltorphin-II (300 nM) and U69593 (300 nM) did so in 13 - 17% of neurons tested. The TRP agonists menthol (400 µM) and icilin (100 µM) both produced a Ca2+-dependent increase in miniature EPSC rate which was unaffected by the voltage dependent calcium channel (VDCC) blocker Cd2+. The proportion of neurons in which deltorphin-II reduced the miniature EPSC rate was enhanced in the presence of icilin (83%), but not menthol (0%). By contrast, the proportion of DAMGO and U69593 responders was unaltered in the presence of menthol (57%, 0%), or icilin (57%, 17%). CONCLUSIONS: These findings demonstrate that δ-opioid receptor activation selectively inhibits inputs activated by icilin, whereas µ-opioid receptor activation has a more widespread effect on synaptic inputs to neurons in the superficial dorsal horn. These findings suggest that δ-opioids may provide a novel analgesic approach for specific, TRPA1-like mediated pain modalities.

Brain circuitry underlying pain in response to imagined movement in people with spinal cord injury.

Pain following injury to the nervous system is characterized by changes in sensory processing including pain. Although there are many studies describing pain evoked by peripheral stimulation, we have recently reported that pain can be evoked in subjects with complete spinal cord injury (SCI) during a motor imagery task. In this study, we have used functional magnetic resonance imaging to explore brain sites underlying the expression of this phenomenon. In 9 out of 11 subjects with complete thoracic SCI and below-level neuropathic pain, imagined foot movements either evoked pain in a previously non-painful region or evoked a significant increase in pain within the region of on-going pain (3.2+/-0.7-5.2+/-0.8). In both controls (n=19) and SCI subjects, movement imagery evoked signal increases in the supplementary motor area and cerebellar cortex. In SCI subjects, movement imagery also evoked increases in the left primary motor cortex (MI) and the right superior cerebellar cortex. In addition, in the SCI subjects, the magnitude of activation in the perigenual anterior cingulate cortex and right dorsolateral prefrontal cortex was significantly correlated with absolute increases in pain intensity. These regions expanded to include right and left anterior insula, supplementary motor area and right premotor cortex when percentage change in pain intensity was examined. This study demonstrates that in SCI subjects with neuropathic pain, a cognitive task is able to activate brain circuits involved in pain processing independently of peripheral inputs.

Primary afferents with TRPM8 and TRPA1 profiles target distinct subpopulations of rat superficial dorsal horn neurones.

BACKGROUND AND PURPOSE: The transient receptor potential (TRP) channels, transient receptor potential melastatin-1 (TRPM8) and transient receptor potential ankyrin-1 (TRPA1), are expressed in subpopulations of sensory neurones and have been proposed to mediate innocuous and noxious cold sensation respectively. The aim of this study was to compare TRPM8 and TRPA1 modulation of glutamatergic afferent transmission within the spinal dorsal horn. EXPERIMENTAL APPROACH: Whole cell patch clamp recordings were made from rat spinal cord slices in vitro to examine the effect of TRP agonists and temperature on glutamatergic excitatory postsynaptic currents (EPSCs). KEY RESULTS: Icilin (3 or 100 micromol.L(-1)), menthol (200 micromol.L(-1)) and capsaicin (1 micromol.L(-1)) reduced the amplitude of primary afferent evoked EPSCs in subpopulations of lamina I and II neurones. In a subpopulation of superficial neurones, innocuous cold (threshold 29 degrees C), 3 micromol.L(-1) icilin (EC50 1.5 micromol.L(-1)) and menthol (EC50 263 micromol.L(-1)) increased the rate of spontaneous miniature EPSCs. In the majority of lamina I and II neurones, 100 micromol.L(-1) icilin (EC50 79 micromol.L(-1)), allyl isothiocyanate (EC50 226 micromol.L(-1)), cinnamaldehyde (EC50 38 micromol.L(-1)) and capsaicin (1 micromol.L(-1)) increased miniature EPSC rate. The response to 100 micromol.L(-1), but not 3 micromol.L(-1) icilin, was abolished by ruthenium red, while neither was affected by iodoresiniferatoxin. Responsiveness to 3 micromol.L(-1), but not to 100 micromol.L(-1) icilin, was highly predictive of innocuous cold responsiveness. Neurones responding to 3 micromol.L(-1) icilin and innocuous cold were located more superficially than those responding to 100 micromol.L(-1) icilin. CONCLUSIONS AND IMPLICATIONS: Activation of TRPM8 and TRPA1 presynaptically modulated glutamatergic transmission onto partially overlapping but distinct populations of superficial dorsal horn neurones. Spinal TRPM8 and TRPA1 channels may therefore provide therapeutic targets in cold hyperesthesia.