Early afferent activity from the facet joint after painful trauma to its capsule potentiates neuronal excitability and glutamate signaling in the spinal cord

Cervical facet joint injury induces persistent pain and central sensitization. Preventing the peripheral neuronal signals that initiate sensitization attenuates neuropathic pain. Yet, there is no clear relationship among facet joint afferent activity, development of central sensitization, and pain, which may be hindering effective treatments for this pain syndrome. This study investigates how afferent activity from the injured cervical facet joint affects induction of behavioral sensitivity and central sensitization. Intra-articular bupivacaine was administered to transiently suppress afferent activity immediately or 4 days after facet injury. Mechanical hyperalgesia was monitored after injury, and spinal neuronal hyperexcitability and spinal expression of proteins that promote neuronal excitability were measured on day 7. Facet injury with saline vehicle treatment induced significant mechanical hyperalgesia (P < .027), dorsal horn neuronal hyperexcitability (P < .026), upregulation of pERK1/2, pNR1, mGluR5, GLAST, and GFAP, and downregulation of GLT1 (P < .032). However, intra-articular bupivacaine immediately after injury significantly attenuated hyperalgesia (P < .0001), neuronal hyperexcitability (P < .004), and dysregulation of excitatory signaling proteins (P < .049). In contrast, intra-articular bupivacaine at day 4 had no effect on these outcomes. Silencing afferent activity during the development of neuronal hyperexcitability (4 hours, 8 hours, 1 day) attenuated hyperalgesia and neuronal hyperexcitability (P < .045) only for the treatment given 4 hours after injury. This study suggests that early afferent activity from the injured facet induces development of spinal sensitization via spinal excitatory glutamatergic signaling. Peripheral intervention blocking afferent activity is effective only over a short period of time early after injury and before spinal modifications develop, and is independent of modulating spinal glial activation.     

Deciphering the role of endogenous opioids in high-frequency TENS using low and high doses of naloxone

Previous human studies have shown that the analgesic effect of high-frequency TENS could not be reversed by low doses of naloxone. The aim of the present study was to reinvestigate the possible contribution of opioid receptors to high-frequency TENS analgesia by using low (0.02 mg/kg) and high (0.14 mg/kg) doses of naloxone. Naloxone (high and low doses) and saline were administered intravenously to young healthy adults using a triple-blind randomized cross-over design. For each visit, TENS (100 Hz, 60 μs) was applied for 25 min to the external surface of the left ankle. TENS intensity was adjusted to obtain strong but comfortable (innocuous) paresthesias. Experimental pain was evoked with a 1 cm² thermode applied on the lateral aspect of the left heel. Subjective pain scores were obtained before, during and after TENS. Because preliminary analyses showed that the order of presentation affected the pattern of results, only the first visit of every participant could be analyzed without fear of contamination from possible carry-over effects. These revealed that TENS maintained its analgesic properties following the injection of saline (p < .001) and the injection of a low dose of naloxone (p < .05). However, when a high dose of naloxone was administered, TENS analgesia was completely blocked (p = .20). These results suggest that high-frequency TENS involves opioid receptors. An insufficient amount of opioid antagonist likely prevented previous human studies from discovering the importance of opioid receptors in producing high-frequency TENS analgesia.     

Hyperalgesia and functional sensory loss in restless legs syndrome

Pain and other sensory signs in patients with restless legs syndrome (RLS) are still poorly understood, as most investigations focus on motor system dysfunctions. This study aimed to investigate somatosensory changes in patients with primary RLS and the restoration of somatosensory function by guideline-based treatment. Forty previously untreated RLS patients were investigated unilaterally over hand and foot using quantitative sensory testing (QST) and were compared with 40 age- and gender-matched healthy subjects. The predominant finding in RLS patients was 3- to 4-fold increase of sensitivity to pinprick stimuli in both extremities (hand: P < .05; foot: P < .001), a sensory pathway involved in withdrawal reflexes. Pinprick hyperalgesia was not paralleled by dynamic mechanical allodynia. Additional significant sensory changes were tactile hypoesthesia in both extremities (hand: P < .05; foot P < .01) and dysesthesia to non-noxious cold stimuli (paradoxical heat sensation), which was present in the foot in an unusually high proportion (14 of 40 patients; P < .01). In 8 patients, follow-up QST 2 to 20 months after treatment with l-DOPA (L-3,4-dihydroxyphenylalanine) revealed a significant reduction of pinprick hyperalgesia (−60%, P < .001), improved tactile detection (+50%, P < .05), and disappearance of paradoxical heat sensation in half of the patients. QST suggested a type of spinal or supraspinal central sensitization differing from neuropathic pain or human experimental models of central sensitization by the absence of dynamic mechanical allodynia. Reversal of pinprick hyperalgesia by l-DOPA may be explained by impaired descending inhibitory dopaminergic control on spinal nociceptive neurons. Restoration of tactile sensitivity and paradoxical heat sensations suggest that they were functional disturbances resulting from central disinhibition.     

Effects of COX inhibition on experimental pain and hyperalgesia during and after remifentanil infusion in humans

Opioids may enhance pain sensitivity resulting in opioid-induced hyperalgesia (OIH). Activation of spinal cyclooxygenase may play a role in the development of OIH. The aim of this study was to demonstrate remifentanil-induced postinfusion hyperalgesia in an electrical pain and a cold pain model, and to investigate whether COX-2 (parecoxib) or COX-1 (ketorolac) inhibition could prevent hyperalgesia after remifentanil infusion. Sixteen healthy males were enrolled in this randomized, double-blind, placebo-controlled crossover study. Each subject went through 4 sessions: control, remifentanil, parecoxib + remifentanil, and ketorolac + remifentanil. Transcutaneous electrical stimulation induced acute pain and areas of pinprick hyperalgesia. The areas of pinprick hyperalgesia were assessed before, during, and after a 30-minute infusion of either remifentanil or saline. The cold-pressor test (CPT) was performed before, at the end of, and 1 hour after the infusions. The subjects received a bolus of either saline, 40 mg parecoxib, or 30 mg ketorolac intravenously after the first CPT. The areas of pinprick hyperalgesia and CPT pain after the end of remifentanil infusion increased significantly compared to control (P < 0.001 and P = 0.005, respectively). Pretreatment with parecoxib or ketorolac reduced the postinfusion area of pinprick hyperalgesia (P < 0.001 and P = 0.001, respectively), compared to the remifentanil group. Parecoxib reduced the area significantly more than ketorolac (P = 0.009). In the CPT, pretreatment with parecoxib or ketorolac did not prevent postinfusion hyperalgesia. These results demonstrated OIH in both models, and may suggest that COX-2 inhibition is more important than COX-1 inhibition in reducing hyperalgesia.     

Metabolite concentrations in the anterior cingulate cortex predict high neuropathic pain impact after spinal cord injury

Persistent pain is a common reason for reduced quality of life after a spinal cord injury (SCI). Biomarkers of neuropathic pain may facilitate translational research and the understanding of underlying mechanisms. Research suggests that pain and affective distress are anatomically and functionally integrated in the anterior cingulate cortex and can modulate sensory and affective aspects of pain. We hypothesized that severe neuropathic pain with a significant psychosocial impact would be associated with metabolite concentrations (obtained by magnetic resonance spectroscopy) in the anterior cingulate cortex, indicating neuronal and/or glial dysfunction. Participants with SCI and severe, high-impact neuropathic pain (SCI-HPI; n = 16), SCI and moderate, low-impact neuropathic pain (SCI-LPI; n = 24), SCI without neuropathic pain (SCI-noNP; n = 14), and able-bodied, pain-free control subjects (A-B; n = 22) underwent a 3-T magnetic resonance imaging brain scan. Analyses revealed that the SCI-HPI group had significantly higher levels of myoinositol (Ins) (P < .000), creatine (P = .007), and choline (P = .014), and significantly lower levels of N-acetyl aspartate/Ins (P = .024) and glutamate-glutamine (Glx)/Ins (P = .003) ratios than the SCI-LPI group. The lower Glx/Ins ratio significantly discriminated between SCI-HPI and the A-B (P = .006) and SCI-noNP (P = .026) groups, displayed excellent test-retest reliability, and was significantly related to greater pain severity, interference, and affective distress. This suggests that the combination of lower glutamatergic metabolism and proliferation of glia and glial activation are underlying mechanisms contributing to the maintenance of severe neuropathic pain with significant psychosocial impact in chronic SCI. These findings indicate that the Glx/Ins ratio may be a useful biomarker for severe SCI-related neuropathic pain with significant psychosocial impact.     

The effects of mexiletine,desipramine and fluoxetine in rat models involving central sensitization

Drugs that are clinically effective (mexiletine and desipramine) or ineffective (fluoxetine) in the treatment of human neuropathic pain were evaluated for efficacy in rat models involving central sensitization (i.e., formalin model and the L5/L6 spinal nerve ligation model of neuropathic pain) using tests that differ in stimulus modality: noxious chemical stimulus (formalin model) as well as noxious (pin prick) and innocuous mechanical stimuli (application of von Frey filaments). Mexiletine (10–100 mg/kg, s.c.) significantly (P<0.05) attenuated hyperalgesia in formalin-treated (60 mg/kg and 100 mg/kg) and neuropathic rats (100 mg/kg) as well as tactile allodynia in neuropathic rats (100 mg/kg). Desipramine (1–100 mg/kg, s.c.), on the other hand, reduced hyperalgesia significantly (P<0.05) in formalin-treated (3, 10, 30 and 100 mg/kg) and neuropathic rats (10 mg/kg and 100 mg/kg), but did not reduce tactile allodynia in the neuropathic rats. Fluoxetine (3–30 mg/kg, s.c.) did not inhibit either hyperalgesia or allodynia in any of the tests employed. Fluoxetine, which is relatively ineffective in reducing neuropathic pain in humans, was also ineffective in reducing hyperalgesia and allodynia associated with central sensitization in rats. Thus, drugs which are effective in reducing human neuropathic pain consistently attenuated hyperalgesia in formalin-treated or neuropathic rats. Desipramine also distinguished mechanical hyperalgesia from tactile allodynia in rats rendered neuropathic by spinal nerve ligation. These data are consistent with the hypothesis that the neuronal mechanisms underlying these two manifestations of neuropathic pain are different     

Contralateral High or a Combination of High- and Low-Frequency Transcutaneous Electrical Nerve Stimulation Reduces Mechanical Allodynia and Alters Dorsal Horn Neurotransmitter Content in Neuropathic Rats

The purpose of the study was to examine the effect of 3 different application strategies for transcutaneous electrical nerve stimulation (TENS) on neuropathy-induced allodynia and dorsal horn neurotransmitter content. Rats were treated with high-frequency, low-frequency, or a combination of high and low-frequency stimulation. TENS was delivered through self-adhesive electrodes daily for 1 hour to rats with a right-sided chronic constriction injury (CCI). Stimulation was delivered to skin or acupuncture points on the left and mechanical and thermal pain thresholds were assessed in the right hind paw. Neurotransmitter content was assessed bilaterally in the dorsal horn of the spinal cord. Daily, high-frequency or a combination of high- and low-frequency TENS reduced mechanical (P < .001), but not thermal allodynia in the right hind paw when compared with untreated CCI rats. Daily high frequency TENS elevated the dorsal horn synaptosomal content of GABA bilaterally (P < .014) and a combination of high- and low-frequency TENS elevated the dorsal horn content of aspartate (P < .001), glutamate (P < .001) and glycine (P < .001) bilaterally over that seen in untreated CCI rats. The present findings support a contralateral approach to the application of TENS and suggest that distinct strategies for TENS application may differentially alter neurotransmission in the central nervous system.PerspectiveBecause CCI rats are reminiscent of humans with neuropathy, daily high or a combination of high- and low-frequency TENS may reduce mechanical allodynia in humans with neuropathic pain. Because the 2 intervention strategies produce distinctive alterations in spinal cord neurotransmitter content, each may represent a distinctive option for treatment.     

Oral administration of the p38α MAPK inhibitor,UR13870, inhibits affective pain behavior after spinal cord injury

The p38α mitogenous activated protein kinase (MAPK) cell signaling pathway is a key mechanism of microglia activation and has been studied as a target for neuropathic pain. The effect of UR13870, a p38α MAPK inhibitor, on microglia expression in the anterior cingulate cortex (ACC) and spinal dorsal horn was addressed after T9 contusion spinal cord injury (SCI) in the rat, in addition to behavioral testing of pain-related aversion and anxiety. Administration of intravenous UR13870 (1 mg/kg i.v.) and pregabalin (30 mg/kg i.v.) reduced place escape avoidance paradigm (PEAP) but did not affect open-field anxiety behavior 42 days after SCI. PEAP behavior was also reduced in animals administered daily with oral UR13870 (10 mg/kg p.o.) and preserved spinal tissue 28 days after SCI. Although UR13870 (10 mg/kg p.o.) failed to reduce OX-42 and glial fibrillar acid protein immunoreactivity within the spinal dorsal horn, a reduction toward the control level was observed close to the SCI site. In the anterior cingulate cortex (ACC), a significant increase in OX-42 immunoreactivity was identified after SCI. UR13870 (10 mg/kg p.o.) treatment significantly reduced OX-42, metabotropic glutamate type 5 receptor (mGluR5), and NMDA (N-methyl-d-aspartate) 2B subunit receptor (NR2B) expression in the ACC after SCI. To conclude, oral treatment with a p38α MAPK inhibitor reduces the affective behavioral component of pain after SCI in association with a reduction of microglia and specific glutamate receptors within the ACC. Nevertheless the role of neuroinflammatory processes within the vicinity of the SCI site in the development of affective neuropathic pain cannot be excluded.     

Pregabalin in severe burn injury pain: a double-blind, randomised placebo-controlled trial

This randomised, double-blind, placebo-controlled trial assessed the efficacy and tolerability of pregabalin to alleviate the neuropathic component of moderate to severe burn pain. Patients aged 18 to 65 years admitted to a burns unit with a 5% or greater total body surface area burn injury were screened to participate in the trial. Using the Neuropathic Pain Scale (NPS), patients scoring 4 or higher on ‘hot’ pain or ‘sharp’ pain were invited to participate. Consenting patients were randomly assigned to receive pregabalin or placebo for 28 days with individual dose titration commencing at 75 mg twice daily to a maximum pregabalin dose of 300 mg twice daily. The primary outcome measure was the patients’ daily response to the sharp and hot pain of the NPS. Secondary outcome measures included the remaining elements of the NPS, daily opioid requirement, length of hospital stay, pain at 6 months, and side effects of nausea, vomiting, drowsiness and giddiness. For patients administered pregabalin, the primary outcome measures hot (P = .01) and sharp (P = .04) pain were significantly reduced compared with those in patients administered placebo. Secondary outcome measures of itch, unpleasantness, surface pain, and procedural pain were significantly lower (P < .05) in the pregabalin group. Adverse effects were uncommon, with no difference between the treatment groups. There was no significant difference between the pregabalin and placebo treatment groups with respect to opioid consumption, duration of hospital stay, or pain at 6 months. Pregabalin was efficacious and well tolerated in patients after severe burn injury and whose pain was characterised by features of acute neuropathic pain.     

Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy

Microglia, the intrinsic macrophages of the central nervous system, have previously been shown to be activated in the spinal cord in several rat mononeuropathy models. Activation of microglia and subsequent release of proinflammatory cytokines are known to play a role in inducing a behavioral hypersensitive state (hyperalgesia and allodynia) in these animals. The present study was undertaken to determine whether minocycline, an inhibitor of microglial activation, could attenuate both the development and existing mechanical allodynia and hyperalgesia in an L5 spinal nerve transection model of neuropathic pain. In a preventive paradigm (to study the effect on the development of hypersensitive behaviors), minocycline (10, 20, or 40 mg/kg intraperitoneally) was administered daily, beginning 1 h before nerve transection. This regimen produced a decrease in mechanical hyperalgesia and allodynia, with a maximum inhibitory effect observed at the dose of 20 and 40 mg/kg. The attenuation of the development of hyperalgesia and allodynia by minocycline was associated with an inhibitory action on microglial activation and suppression of proinflammatory cytokines at the L5 lumbar spinal cord of the nerveinjured animals. The effect of minocycline on existing allodynia was examined after its intraperitoneal administration initiated on day 5 post-L5 nerve transection. Although the postinjury administration of minocycline significantly inhibited microglial activation in neuropathic rats, it failed to attenuate existing hyperalgesia and allodynia. These data demonstrate that inhibition of microglial activation attenuated the development of behavioral hypersensitivity in a rat model of neuropathic pain but had no effect on the treatment of existing mechanical allodynia and hyperalgesia.     

Cholecystokinin receptors mediate tolerance to the analgesic effect of TENS in arthritic rats

Transcutaneous electrical nerve stimulation (TENS) is a treatment for pain that involves placement of electrical stimulation through the skin for pain relief. Previous work from our laboratory shows that repeated application of TENS produces analgesic tolerance by the fourth day and a concomitant cross-tolerance at spinal opioid receptors. Prior pharmacological studies show that blockade of cholecystokinin (CCK) receptors systemically and spinally prevents the development of analgesic tolerance to repeated doses of opioid agonists. We therefore hypothesized that systemic and intrathecal blockade of CCK receptors would prevent the development of analgesic tolerance to TENS, and cross-tolerance at spinal opioid receptors. In animals with knee joint inflammation (3% kaolin/carrageenan), high (100 Hz) or low frequency (4 Hz) TENS was applied daily and the mechanical withdrawal thresholds of the muscle and paw were examined. We tested thresholds before and after inflammation, and before and after TENS. Animals treated systemically, prior to TENS, with the CCK antagonist, proglumide, did not develop tolerance to repeated application of TENS on the fourth day. Spinal blockade of CCK-A or CCK-B receptors blocked the development of tolerance to high and low frequency TENS, respectively. In the same animals we show that spinal blockade of CCK-A receptors prevents cross-tolerance at spinal delta-opioid receptors that normally occurs with high frequency TENS; and blockade of CCK-B receptors prevents cross-tolerance at spinal mu-opioid receptors that normally occurs with low frequency TENS. Thus, we conclude that blockade of CCK receptors prevents the development of analgesic tolerance to repeated application of TENS in a frequency-dependent manner.     

Gabapentin Alleviates Facet-Mediated Pain in the Rat Through Reduced Neuronal Hyperexcitability and Astrocytic Activation in the Spinal Cord

Although joint pain is common, its mechanisms remain undefined, with little known about the spinal neuronal responses that contribute to this type of pain. Afferent activity and sustained spinal neuronal hyperexcitability correlate to facet joint loading and the extent of behavioral sensitivity induced after painful facet injury, suggesting that spinal neuronal plasticity is induced in association with facet-mediated pain. This study used a rat model of painful C6-C7 facet joint stretch, together with intrathecal administration of gabapentin, to investigate the effects of one aspect of spinal neuronal function on joint pain. Gabapentin or saline vehicle was given via lumbar puncture prior to and at 1 day after painful joint distraction. Mechanical hyperalgesia was measured in the forepaw for 7 days. Extracellular recordings of neuronal activity and astrocytic and microglial activation in the cervical spinal cord were evaluated at day 7. Gabapentin significantly (P = .0001) attenuated mechanical hyperalgesia, and the frequency of evoked neuronal firing also significantly decreased (P < .047) with gabapentin treatment. Gabapentin also decreased (P < .04) spinal glial fibrillary acidic protein expression. Although spinal Iba1 expression was doubled over sham, gabapentin did not reduce it. Facet joint–mediated pain appears to be sustained through spinal neuronal modifications that are also associated with astrocytic activation.     

Transcutaneous Electric Nerve Stimulation Reduces Acute Postoperative Pain and Analgesic Use After Open Inguinal Hernia Surgery: A Randomized,Double-Blind,Placebo-Controlled Trial

In this randomized, double-blind, placebo-controlled trial, we evaluated the role of transcutaneous electrical nerve stimulation (TENS) in the multimodal treatment (nonopioid analgesics and kinesiotherapy) of postoperative pain following open inguinal hernia repair.In total, 80 males participants with elective primary unilateral hernia Lichtenstein repair were randomly allocated to receive TENS or a placebo-TENS procedure. The TENS group received local and segmental conventional TENS on the first and second postoperative days. In the placebo-TENS group, intensity was set at 0 to 0.5mA. Change of pain level at rest, when walking, when standing up from bed, pressure algometry parameters and additional analgesic use were the main outcomes.Reduction of VAS pain score and absolute and relative pain relief were observed in the TENS group following the procedures compared to the placebo-TENS group (P< .001). The pressure pain threshold and maximal tolerable pressure in the hernia side were equal before the TENS procedure in both groups (P= .84), but after the procedure, these were higher in TENS group (P< .001). Additional nonopioid analgesics requirements were lower in the TENS group on the first and second postoperative days (P< .001).TENS is a safe procedure that can reduce postoperative pain and analgesic use after open inguinal hernia repair.The study was registered in the database of clinicaltrials.gov (register number NCT03739060).PerspectiveThis article presents TENS as a safe and effective nonpharmacologic intervention to reduce postoperative pain after open inguinal hernia repair. TENS could be used in daily practice as part of a multimodal postoperative pain treatment, especially for patients suffering from hyperalgesia.     

Above-level mechanical hyperalgesia in rats develops after incomplete spinal cord injury but not after cord transection, and is reversed by amitriptyline, morphine and gabapentin

Spinal cord injury (SCI) is a major cause of persistent neuropathic pain of central origin. Recent evidence suggests neuropathic pain in clinically complete SCI patients correlates with limited sensory function below the lesion (sensory discomplete). On this basis we examined if the onset of mechanical hyperalgesia was different in rodents after a severe incomplete clip-compression SCI versus a complete spinal cord transection at thoracic segment T13. Above-level withdrawal behaviors evoked by forepaw stimulation provided evidence of mechanical hyperalgesia after incomplete but not complete SCI, whereas below-level responses evoked by hindpaw stimulation revealed hypersensitivity after both injuries. The latency of the above-level response was 4-5 wks but was longer after a moderate clip-compression injury. Mechanical hyperalgesia was fully reversed by three analgesic drugs used in treating neuropathic SCI pain, but their duration of action differed significantly, showing a rank order of amitriptyline (24-48 h) ? morphine (6 h) > gabapentin (2 h). Evidence of central sensitization in cervical spinal cord segments that receive sensory projections from the forelimbs was provided by immunohistochemistry for Zif268, a functional marker of neuroplasticity. Zif268-immunoreactive neurons in laminae I/II increased in response to repetitive noxious forepaw stimulation in the incomplete SCI group, and this response was reduced in the complete transection and sham-operated groups. These data are consistent with the hypothesis that neuropathic pain of cord origin is more likely to develop after SCI when there is an incomplete loss of axons traversing the lesion.     

The specific disease burden of neuropathic pain: results of a French nationwide survey

We report the first nationwide survey of the impact of neuropathic pain, as opposed to nonneuropathic pain, on quality of life and health care utilization in the French general population. A postal questionnaire was sent to a representative sample of 4554 respondents from an initial nationwide survey of 30,155 subjects with or without chronic pain. It included pain characteristics (Neuropathic Pain Symptom Inventory, DN4), quality of life (Medical Outcomes Short Form 12, SF-12), sleep, anxiety/depressive symptoms (Hospital Anxiety and Depression Scale) and health care utilization. In total, 3899 (85.6%) questionnaires were returned, 3816 (97.9%) could be assessed and 3165 subjects (82.9%) confirmed their pain status. Subjects reporting pain and neuropathic characteristics based on the DN4 displayed a higher degree of impairment of all dimensions relating to quality of life and sleep and had higher anxiety/depression scores than those reporting pain without neuropathic characteristics and those without pain (P < .01). They also made greater use of health care facilities, particularly as concerned neurological treatments and visits to neurologists (21% vs 9%; P < .01). Multivariate analyses showed that the neuropathic characteristics of pain made an independent contribution to quality-of-life impairment (P < .0001 and P = .0005 for the physical and mental scores of the SF-12 respectively). Our study indicates that the disease burden of chronic pain depends on the nature of the pain, independently of its intensity and duration.     

Self-reported somatosensory symptoms of neuropathic pain in fibromyalgia and chronic widespread pain correlate with tender point count and pressure-pain thresholds

Widespread pain and pain hypersensitivity are the hallmark of fibromyalgia, a complex pain condition linked to central sensitization. In this study the painDETECT questionnaire (PDQ), validated to identify neuropathic pain and based on pain quality items, was applied in a cross-sectional sample of patients with chronic widespread pain (CWP). The aims of the study were to assess the patient-reported sensory neuropathic symptoms by PDQ and to correlate these with tender point (TP) count and pressure-pain thresholds. Eighty-one patients (75 F, 6 M) with CWP (ACR-criteria) filled in the PDQ. Manual TP examination was conducted according to ACR guidelines. Computerized cuff pressure algometry was used for the assessment of pressure-pain detection thresholds (PDT, unit: kPa) and pressure-pain tolerance thresholds (PTT, unit: kPa). Mean TP count was 14.32 (range: 2-18), mean PDQ score 22.75 (range: 5-37). Mean PDT was 8.8 kPa (range: 2-36) and mean PTT 30.9 kPa (range: 4-85). Deep-tissue hyperalgesia was the predominant somatosensory symptom reported in 83%, but other neuropathic symptoms were also frequent, e.g. burning 51% and prickling 47%. Statistically significant correlations were found between PDQ score and TP count: r = 0.35 (p < 0.01), and PDQ score and PDT: r = 0.45 (p < 0.01), and PTT: r = 0.43 (p < 0.01). The study indicates that pain in CWP has neuropathic features, and that the presence and number of tender points are associated with neuropathic pain symptoms. A high mean PDQ score was found to correlate with TP count and pressure-pain thresholds. The PDQ may become a useful tool assisting in the identification of central sensitization in patients with CWP and in the future diagnostic assessment fibromyalgia.     

Hemiplegic shoulder pain: Evidence of a neuropathic origin

Hemiplegic shoulder pain (HSP) is common after stroke. Whereas most studies have concentrated on the possible musculoskeletal factors underlying HSP, neuropathic aspects have hardly been studied. Our aim was to explore the possible neuropathic components in HSP, and if identified, whether they are specific to the shoulder or characteristic of the entire affected side. Participants included 30 poststroke patients, 16 with and 14 without HSP, and 15 healthy controls. The thresholds of warmth, cold, heat-pain, touch, and graphesthesia were measured in the intact and affected shoulder and in the affected lower leg. They were also assessed for the presence of allodynia and hyperpathia, and computed tomography/magnetic resonance imaging scans of the brain were reviewed. In addition, chronic pain was characterized. Participants with HSP exhibited higher rates of parietal lobe damage (P < 0.05) compared to those without HSP. Both poststroke groups exhibited higher sensory thresholds than healthy controls. Those with HSP had higher heat-pain thresholds in both the affected shoulder (P < 0.001) and leg (P < 0.01), exhibited higher rates of hyperpathia in both these regions (each P < 0.001), and more often reported chronic pain throughout the affected side (P < 0.001) than those without HSP. The more prominent sensory alterations in the shoulder region suggest that neuropathic factors play a role in HSP. The clinical evidence of damage to the spinothalamic-thalamocortical system in the affected shoulder and leg, the presence of chronic pain throughout the affected side, and the more frequent involvement of the parietal cortex all suggest that the neuropathic component is of central origin.     

One night of total sleep deprivation promotes a state of generalized hyperalgesia: A surrogate pain model to study the relationship of insomnia and pain

Sleep disturbances are highly prevalent in chronic pain patients. Understanding their relationship has become an important research topic since poor sleep and pain are assumed to closely interact. To date, human experimental studies exploring the impact of sleep disruption/deprivation on pain perception have yielded conflicting results. This inconsistency may be due to the large heterogeneity of study populations and study protocols previously used. In addition, none of the previous studies investigated the entire spectrum of nociceptive modalities. To address these shortcomings, a standardized comprehensive quantitative sensory protocol was used in order to compare the somatosensory profile of 14 healthy subjects (6 female, 8 male, 23.5 ± 4.1 year; mean ± SD) after a night of total sleep deprivation (TSD) and a night of habitual sleep in a cross-over design. One night of TSD significantly increased the level of sleepiness (P < 0.001) and resulted in higher scores of the State Anxiety Inventory (P < 0.01). In addition to previously reported hyperalgesia to heat (P < 0.05) and blunt pressure (P < 0.05), study participants developed hyperalgesia to cold (P < 0.01) and increased mechanical pain sensitivity to pinprick stimuli (P < 0.05) but no changes in temporal summation. Paradoxical heat sensations or dynamic mechanical allodynia were absent. TSD selectively modulated nociception, since detection thresholds of non-nociceptive modalities remained unchanged. Our findings show that a single night of TSD is able to induce generalized hyperalgesia and to increase State Anxiety scores. In the future, TSD may serve as a translational pain model to elucidate the pathomechanisms underlying the hyperalgesic effect of sleep disturbances.     

CXCL13 drives spinal astrocyte activation and neuropathic pain via CXCR5

Recent studies have implicated chemokines in microglial activation and pathogenesis of neuropathic pain. C-X-C motif chemokine 13 (CXCL13) is a B lymphocyte chemoattractant that activates CXCR5. Using the spinal nerve ligation (SNL) model of neuropathic pain, we found that CXCL13 was persistently upregulated in spinal cord neurons after SNL, resulting in spinal astrocyte activation via CXCR5 in mice. shRNA-mediated inhibition of CXCL13 in the spinal cord persistently attenuated SNL-induced neuropathic pain. Interestingly, CXCL13 expression was suppressed by miR-186-5p, a microRNA that colocalized with CXCL13 and was downregulated after SNL. Spinal overexpression of miR-186-5p decreased CXCL13 expression, alleviating neuropathic pain. Furthermore, SNL induced CXCR5 expression in spinal astrocytes, and neuropathic pain was abrogated in Cxcr5^–/– mice. CXCR5 expression induced by SNL was required for the SNL-induced activation of spinal astrocytes and microglia. Intrathecal injection of CXCL13 was sufficient to induce pain hypersensitivity and astrocyte activation via CXCR5 and ERK. Finally, intrathecal injection of CXCL13-activated astrocytes induced mechanical allodynia in naive mice. Collectively, our findings reveal a neuronal/astrocytic interaction in the spinal cord by which neuronally produced CXCL13 activates astrocytes via CXCR5 to facilitate neuropathic pain. Thus, miR-186-5p and CXCL13/CXCR5-mediated astrocyte signaling may be suitable therapeutic targets for neuropathic pain.