Development Of Persistent Pain Research Articles

Involvement of nerve injury and activation of peripheral glial cells in tetanic sciatic stimulation‐induced persistent pain in rats

Tetanic stimulation of the sciatic nerve (TSS) produces long-lasting pain hypersensitivity in rats. Long-term potentiation (LTP) of C- and A-fiber-evoked field potentials in the spinal cord has been explored as contributing to central sensitization in pain pathways. However, the peripheral mechanism underlying TSS-induced pain hypersensitivity remains largely unknown. We investigated the effect of TSS on peripheral nerve and the expression of activating transcription factor 3 (ATF3) in dorsal root ganglion (DRG) as a marker of neuronal injury. TSS induced a mechanical allodynia for at least 35 days and induced ATF3 expression in the ipsilateral DRG. ATF3 is colocalized with NF200-labeled myelinated DRG neurons or CGRP- and IB4-labeled unmyelinated ones. Furthermore, we found that TSS induced Wallerian degeneration of sciatic nerve at the level of myelinisation by S100 protein (to label Schwann cells) immunohistochemistry, luxol fast blue staining, and electron microscopy. TSS also elicited the activation of satellite glial cells (SGCs) and enhanced the colocalization of GFAP and P2X7 receptors. Repeated local treatment with tetrodotoxin decreased GFAP expression in SGCs and behavioral allodynia induced by TSS. Furthermore, reactive microglia and astrocytes were found in the spinal dorsal horn after TSS. These results suggest that TSS-induced nerve injury and glial activation in the DRG and spinal dorsal horn may be involved in cellular mechanisms underlying the development of persistent pain after TSS and that TSS-induced nerve injury may be used as a novel neuropathic pain model.

P.1.c.002 Biological peculiarities of the analgesic drug – nefopam in rats

Previous findings indicate that the brain stem descending system becomes more active in modulating spinal nociceptive processes during the development of persistent pain. The present study further identified the supraspinal sites that mediate enhanced descending modulation of behavior hyperalgesia and dorsal horn hyperexcitability (as measured by Fos-like immunoreactivity) produced by subcutaneous complete Freund's adjuvant (CFA). Selective chemical lesions were produced in the nucleus raphe magnus (NRM), the nuclei reticularis gigantocellularis (NGC), or the locus coeruleus/subcoeruleus (LC/SC). Compared to vehicle-injected animals with injection of vehicle alone, microinjection of a serotoninergic neurotoxin 5,7-dihydroxytryptamine into the NRM significantly increased thermal hyperalgesia and Fos protein expression in lumbar spinal cord after hindpaw inflammation. In contrast, the selective bilateral destruction of the NGC with a soma-selective excitotoxic neurotoxin, ibotenic acid, led to an attenuation of hyperalgesia and a reduction of inflammation-induced spinal Fos expression. Furthermore, if the NGC lesion was extended to involve the NRM, the behavioral hyperalgesia and CFA-induced Fos expression were similar to that in vehicle-injected rats. Bilateral LC/SC lesions were produced by microinjections of a noradrenergic neurotoxin, DSP-4. There was a significant increase in inflammation-induced spinal Fos expression, especially in the ipsilateral superficial dorsal horn following LC/SC lesions. These results demonstrated that multiple specific brain stem sites are involved in descending modulation of inflammatory hyperalgesia. Both NRM and LC/SC descending pathways are major sources of enhanced inhibitory modulation in inflamed animals. The persistent hyperalgesia and neuronal hyperexcitability may be mediated in part by a descending pain facilitatory system involving NGC. Thus, the intensity of perceived pain and hyperalgesia is fine-tuned by descending pathways. The imbalance of these modulating systems may be one mechanism underlying variability in acute and chronic pain conditions.

Molecular depletion of descending serotonin unmasks its novel facilitatory role in the development of persistent pain.

Recent studies indicate that persistent pain after tissue or nerve injury is accompanied by an enhanced net descending facilitatory drive that contributes to an amplification and spread of pain. Although 5-HT-containing neurons in the rostral ventromedial medulla (RVM) provide the major descending serotonergic projection to the spinal cord, it is not clear whether the neurotransmitter 5-HT itself released from RVM-spinal neurons contributes to descending pain modulation. In the present study, we determined the role of the descending 5-HT in rat nocifensive behaviors after persistent pain by selectively depleting functional phenotypes of 5-HT in RVM neurons with regional shRNA interference (RNAi) of tryptophan hydroxylase-2 (Tph-2), the rate-limiting enzyme in the synthesis of neuronal 5-HT. Compared to negative control shRNA, Tph-2 shRNA induced significantly prolonged downregulation of Tph-2 in the RVM and 5-HT in spinal dorsal horn. The 5-HT-depleted rats showed normal pain sensitivity in responses to acute noxious stimulation. However, the same RNAi treatment attenuated formalin-induced spontaneous nocifensive responses and tissue or nerve injury-induced allodynia and hyperalgesia. Furthermore, in control shRNA-treated animals, intra-RVM microinjection of brain-derived neurotrophic factor produced a reversible hyperalgesia, which was completely prevented by Tph-2 RNAi pretreatment. Descending inhibition induced by intra-RVM electrical stimulation, but not microinjection of the mu- or kappa-opioid receptor agonists in control shRNA-treated animals was eliminated in 5-HT-depleted rats. These results indicate that the descending 5-HT from the RVM is an important contributor to pain facilitation during the development of persistent pain, and may not mediate opioid-induced descending inhibition in acute pain.

Wide‐dynamic‐range neurons are heterogeneous in windup responsiveness to changes in stimulus intensity and isoflurane anesthesia level in mice

The windup phenomenon in wide-dynamic-range (WDR) neurons represents a short-term neuronal sensitization to repetitive noxious inputs that may share similar mechanisms with those that trigger the development of persistent pain and hyperalgesia. Some WDR cells are readily sensitized and express prominent windup (windup(+)), whereas others do not (windup(-)). We recorded extracellular single-unit activity of deep laminae WDR neurons (350-700 microm) in C57BL/6 mice to determine how changes in stimulus intensity (1x and >2x C-component threshold, n = 53) and concentrations of isoflurane anesthesia (2.0% and 1.0%, n = 30) might differently modulate windup responsiveness in windup(+) and windup(-) cells. Two principally different analysis methods [absolute windup (the number of action potentials) and relative windup (the percentage of action potentials evoked by the first stimulus of the train)] were used to interpret windup data. We observed that increasing the stimulus intensity and decreasing the isoflurane concentration: 1) facilitated windup generation at 0.2-Hz stimulation and significantly enhanced absolute windup at both 0.2-Hz and 0.5-Hz stimulation predominantly in windup(+) cells but did not confer windup capability on windup(-) cells and 2) significantly increased relative windup at 0.2-Hz, but not 0.5-Hz, stimulation in windup(+) cells. Our findings advance our understanding of the neurobiology of deep WDR neurons in mice and demonstrate that two populations of cells differ in their windup responsiveness to changes in experimental conditions. We also elucidate the usefulness and potential limitations of two widely used methods for calculating and presenting windup data.

The influence of ATP-binding cassette sub-family B member -1 (ABCB1) genetic polymorphisms on acute and chronic pain after intrathecal morphine for caesarean section: a prospective cohort study

Background Polymorphisms of the ATP-binding cassette sub-family B member -1 (ABCB1) gene that codes for P-glycoprotein could influence the efflux of morphine from the central nervous system affecting its analgesic action. We investigated the effect of ABCB1 gene polymorphisms on analgesia and the development of persistent pain in post caesarean patients. Methods Women of Chinese descent who received spinal anaesthesia with intrathecal morphine for elective caesarean section were recruited. They were given intravenous morphine via a patient-controlled analgesia pump for postoperative analgesia. Blood samples were collected and analysed for the presence of C1236T, G2677T/A and C3435T single nucleotide polymorphisms of the ABCB1 gene. We primarily investigated the association between ABCB1 polymorphisms and the effect of morphine. In a postpartum phone survey of the subjects six months after surgery, the occurrence of persistent abdominal wound scar pain was established. Results We found no significant statistical difference in total morphine consumption, pain scores and side effects among the various genotypes. For C3435T polymorphism, there was a trend towards the association of the T allele and persistent pain for three months after surgery but this did not reach statistical significance ( P = 0.07). The TT genotype had the longest mean survival time of wound pain in comparison with CT and CC genotypes ( P = 0.004 and P = 0.014, respectively). Conclusion Polymorphisms of ABCB1 were not associated with differences in morphine use in the first 24 h after surgery. Women with the T allele of C3435T polymorphism showed a trend towards a higher risk of developing persistent postoperative pain.

Predicting Postoperative Pain Based on Preoperative Pain Perception

Predicting Postoperative Pain Based on Preoperative Pain Perception

Persistent pain following knee arthroplasty

The prevalence of persistent pain after orthopaedic surgery has been the subject of only few studies and the risk factors for persistent pain have been evaluated even more rarely. The purpose of the present study was to evaluate the degree and the risk factors of persistent pain after knee arthroplasty. The prevalence of persistent postoperative pain after knee replacement was evaluated with a questionnaire in a large, register-based cross-sectional prevalence study. The main hypothesis was that the type of operation (primary, bilateral, revision) would influence the prevalence of persistent postoperative pain. Logistic regression analysis was performed to test the hypothesis and to find other possible risk factors for the development of persistent pain. The total number of patients was 855. The operation was a primary arthroplasty in 648 patients (75.7%), a bilateral arthroplasty in 137 patients (21.1%) and a revision arthroplasty in 70 patients (8.2%). The response rate was 65.7%. The type of operation was not associated with the prevalence of persistent pain, but the degree of early postoperative pain was the strongest risk factor. If the degree of pain during the first postoperative week was from moderate to intolerable, the risk for the development of persistent pain was three to 10 times higher compared with patients complaining of mild pain during the same period. Other risk factors were the long duration of preoperative pain and female sex. Intensity of early postoperative pain and delayed surgery increase the risk of the persistent pain after knee arthroplasty.

Loose ligation of the rat sciatic nerve elicits early accumulation of Shank1 protein in the post-synaptic density of spinal dorsal horn neurons

Plasticity in the spinal dorsal horn may contribute to the development of pain following peripheral nerve injury. Shank proteins are a constituent family of the post-synaptic density (PSD), and they may play a role in synaptic plasticity through activity-dependent synaptic remodeling and growth. In this study we examined the early consequences of the loose ligation of the sciatic nerve on Shank1 protein and message levels in the PSD of spinal dorsal horn neurons. Four hours after sciatic ligation, the protein levels of Shank1 increased in the ipsilateral PSD of ligated animals. In contrast, no changes were detected in the contralateral PSD of these ligated animals, or either the ipsilateral or contralateral PSD of sham-operated animals. Shank1 was linked to the PSD marker protein PSD-95 and the NR2B subunit of NMDA receptors. The ligated animals also exhibited two early signs of pain behavior, a shift in weight distribution and thermal hyperalgesia. There was no overall change in Shank1 message in either ligated or sham-operated animals. The accumulation of Shank1 in the PSD was abolished by intrathecal pre-treatment with anisomycin or Shank1 siRNA, but not with non-target siRNA. The same pre-treatment prevented both the early signs of pain behavior. Intrathecal pre-treatment with either MK-801 or U0126 similarly prevented the Shank1 accumulation and alleviated both the behavioral signs of pain. The early accumulation of Shank1 in the PSD of dorsal horn neurons may be a necessary step in the injury-associated plasticity that in time leads to the development of persistent pain.

Emerging Importance of Neuron-Satellite Glia Interactions within Trigeminal Ganglia in Craniofacial Pain

Pain in the head and face, which can be very severe and debilitating, often involves activation of trigeminal ganglion nerves. The craniofacial symptoms can manifest as acute or transient conditions such as toothaches and headaches, or can transform into more chronic conditions such as migraine, rhinosinusitis, temporomandibular joint (TMJ) disorder, or trigeminal neuralgia. Traditionally, it is known that peripheral tissue injury or inflammation leads to excitation of trigeminal nerves that release inflammatory molecules in the periphery as well as facilitate transmission of nociceptive signals to the central nervous system. However, findings from recent studies have demonstrated that peripheral tissue injury or inflammation also leads to increased interactions between neuronal cell bodies and satellite glial cells within the trigeminal ganglion. These cell-to-cell interactions, which involve the transfer of key regulatory mediators via channels or gap junctions as well as paracrine signaling, are thought to play an important role in the induction and maintenance of peripheral sensitization of trigeminal nociceptors. The focus of this review will be on understanding the importance of the increased signaling between neuronal cell bodies and satellite glia cells in trigeminal ganglia to the development of persistent pain.

Applying dialectical behavior therapy to chronic pain: A case study

Background and aims Chronic pain patients often present with a host of psychological and somatic problems and are unable to work despite receiving traditional pain management. For example, it is common that patients with persistent pain also suffer from a variety of anxiety and depressive symptoms. Indeed, the regulation of emotions may be one important factor that is associated with the development of persistent pain. Dialectical behavior therapy, a form of cognitive-behavioral therapy, focuses on emotion regulation and has successfully addressed other complex problems. The objective of this case study was to test the feasibility of developing and applying a dialectical behavior therapy approach to chronic pain. Methods: Feasibility study of n = 1 A 52-year-old adult suffering musculoskeletal pain, work disability, depression, and mood swings was offered therapy. She had not worked at her occupation for 10 years. An intervention was developed based on dialectical behavior therapy that included goal setting, validation, behavioral experiments and interoceptive exposure. Goals were developed with the client, based on her own values, and these were to: increase participation in previously enjoyable activities, not only reduce but also accept that some pain may remain, and, express and regulate emotions. Validation (understanding the patient's situation) and psychoeducation were used to analyze the problem with the patient in focus. Function was approached by monitoring activities and conducting dialectical behavioral experiments where the patient systematically approached activities she no longer participated in (exposure). Emotional regulation followed a training program developed in dialectical behavior therapy designed to have people experience, express, and manage a variety of positive and negative emotions. In order to address the patient's complaint that she avoided her own feelings as well as the pain, interoceptive exposure was introduced. After establishing calm breathing, the client was asked to focus attention on the negative feelings or pain as a way of de-conditioning the psychological responses to them. Therapy was conducted during 16 sessions over a six-month period. Results Improvements were seen on the main outcome variables. Pain intensity ratings dropped from 4.3 during the baseline to almost 0 at the end of treatment. Function increased as the patient participated in goal activities. Depression scores were decreased from 26 (Beck's Depression Inventory) at pre treatment to 5 at follow-up, which falls within the normal range. Similarly, catastrophizing and fear decreased on standardized scales and fell within the range of a nonclinical population. Ratings indicated that acceptance of the pain increased over the course of therapy. Sleep improved and was also within the normal range according to scores on the Insomnia Severity Index. The patient reported seeking and obtaining employment as well. At the three-month follow-up improvements were maintained. Conclusions This case shows that dialectical behavior therapy may be feasible for people suffering persistent pain with multiple problems such as pain, depression, and emotion regulation. However, since this is a case study, the validity of the findings has not yet been established. The positive results, however, warrant the further investigation of the application of these techniques to complex chronic pain cases.

Early Changes in Homer1 Proteins in the Spinal Dorsal Horn Are Associated with Loose Ligation of the Rat Sciatic Nerve

Plasticity in the spinal dorsal horn is thought to underlie, at least in part, pain behavior after peripheral nerve injury. Homer1 proteins play an important role in synaptic plasticity through an activity-dependent remodeling of the postsynaptic density (PSD). In this study, we examined the early consequences of the loose ligation of the sciatic nerve on the levels of Homer1a and Homer1b/c proteins in the PSD of spinal dorsal horn neurons. Male rats were randomly assigned to control, sham-operated, or ligated groups. Four hours after sciatic exposure or ligation, the animals were anesthetized and killed. Dorsal horn ipsilateral and contralateral quadrants were homogenized and centrifuged to obtain a PSD-containing LP1 fraction. Homer1 isoforms were identified in Western immunoblots. In some animals, Homer1 small interfering RNA (siRNA), nontarget siRNA, MK-801, or U01026 was injected intrathecally before surgery to assess the effects of this treatment on the levels of Homer1 isoforms and on 2 signs of injury-associated pain behavior, a shift in weight-bearing distribution and thermal hyperalgesia. In ligated animals, the protein levels of Homer1a increased and those of Homer1b/c decreased in the ipsilateral LP1 fraction of the spinal dorsal horn. In contrast, no changes were detected in the contralateral LP1 fraction of ligated animals or the ipsilateral or contralateral LP1 fraction of sham-operated animals. Intrathecal injections of Homer1 siRNA, but not nontarget siRNA, 2 h before the ligation prevented the accumulation of Homer1a and loss of Homer1b/c in the ipsilateral LP1 fraction. The same pretreatment with Homer1 siRNA also alleviated both a shift in weight-bearing behavior and thermal hyperalgesia in the ligated animals. Intrathecal injections of MK-801 or U0126 15 min before the ligation similarly prevented the injury-associated changes in Homer1 protein levels and the behavioral signs of pain. The ligation-associated changes in the protein levels of Homer1a and Homer1b/c in the ipsilateral PSD of spinal dorsal horn neurons may be an important early reflection of the injury-associated plasticity that in time leads to the development of persistent pain.

Persistent pain after caesarean section and vaginal birth: a cohort study

Background Although persistent pain has been described to occur after various types of surgery, little is known about this entity following caesarean section or vaginal birth. We sought to examine the association between mode of delivery and development of persistent pain, as well as the nature and intensity of the pain. Methods A questionnaire was sent to 600 consecutive Finnish-speaking women within one year of their giving birth. The survey recorded the women’s health history, obstetric history, previous pain, details of the caesarean section or vaginal birth, and a description of their pain, if present. Results Persistent pain one year after delivery was significantly more common after caesarean section (42/229, 18%) than after vaginal birth (20/209, 10%: P = 0.011, OR 2.1 with 95% CI 1.2-3.7). The persistent pain was mild in 55% of the patients in both groups, and intense or unbearable for four caesarean sections and six vaginal births. Persistent pain was significantly more common in women with previous pain ( P = 0.013), previous back pain ( P = 0.016), and any chronic disease ( P = 0.016). The women with persistent pain recalled significantly more pain on the day after caesarean section ( P = 0.004) and vaginal birth ( P = 0.001) than those who did not report persistent pain. Conclusion Persistent pain is more common one year after a caesarean section than after vaginal birth. A history of previous pain and pain on the day after delivery correlated with persistent pain.

The Analgesic Properties of Scalp Infiltrations with Ropivacaine After Intracranial Tumoral Resection

The issue of postoperative pain after neurosurgery is controversial. It has been reported as mild to moderate and its treatment may be inadequate. Infiltration of the surgical site with local anesthetics has provided transient benefit after craniotomy, but its effect on chronic pain has not been evaluated. Accordingly, we designed the present study to test the hypothesis that ropivacaine infiltration of the scalp reduces acute and persistent postoperative pain after intracranial tumor resection. This was a prospective, single-blinded study. Inclusion criteria were intracranial tumor resection, age > or = 18 or < or = 80 yr, and ability to understand and use a visual analog scale (VAS). Exclusion criteria were history of craniotomy, chronic drug abuse, and neurologic disorders. All eligible patients were randomly included in Group I (infiltration) or C (control). Postoperative analgesia was IV acetaminophen combined with nalbuphine. At the end of the surgery, Group I received an infiltration of the surgical site with 20 mL of ropivacaine 0.75%. Acute pain was evaluated hourly by VAS during the first 24 h. The analgesic effect of ropivacaine was evaluated based on total consumption of nalbuphine and VAS scores. The incidence of persistent pain and neuropathic pain was assessed at the 2-mo postoperative evaluation. We used the Student's t-test to compare total nalbuphine consumption, repeated measures analysis of variance with post hoc Bonferroni t-test for VAS score and the Fisher's exact test for chronic and neuropathic pain. Fifty-two patients were enrolled, 25 in Group I and 27 in Group C. Demographic and intraoperative data were similar between groups. Group I showed a nonsignificant trend toward reduced nalbuphine consumption during the first postoperative day, 11.2 +/- 9.2 mg vs 16.6 +/- 11.0 mg for Group C (mean +/- SD, P = 0.054). VAS scores were significantly higher in Group C. Two months after surgery, persistent pain was significantly lower in Group I, 2/24 (8%) vs 14/25 (56%), P = 0.0003. One patient (4.1%) in Group I versus six (25%) patients in Group C (P = 0.04) experienced neuropathic pain. Because pain is moderate after intracranial tumor resection, there is limited interest in scalp infiltrations with ropivacaine in the acute postoperative period. Nevertheless, these infiltrations may be relevant for the rehabilitation of neurosurgical patients and their quality of life by limiting the development of persistent pain and particularly neuropathic pain.

The c-kit signaling pathway is involved in the development of persistent pain

Protein kinase signal transduction pathways play critical roles in regulating nociception. Here we show that c-kit, a tyrosine kinase receptor, is expressed in lamina I and II layer of the dorsal horn. Moreover, the superficial c-kit+ fibers originate from the dorsal root ganglion, and c-kit in lamina II inner layer comes from intrinsic expression of the spinal cord. KitW-v mice, which contain a hypomorphic mutation, exhibited normal acute pain in most pain behavior tests. In the formalin test, the first phase was not affected, whereas the second phase pain response of KitW-v mice was significantly reduced relative to wild-type littermates. KitW-v mice also showed abnormal neuropathic pain, notably in the contralateral side of nerve injury. The expression and release of CGRP and substance P were not altered by the c-kit mutation. Together, these results implicate c-kit-mediated signal transduction in the development of persistent pain.

Pain catastrophizing and cortisol resposnes to laboratory pain testing among temporomandibular disorder and healthy, pain-free participants

Pain catastrophizing is associated with adverse pain-related outcomes and, in many instances, exaggerated sensitivity to laboratory pain testing. In a recent study of healthy, pain-free participants, pain catastrophizing was not correlated with cortisol responses, suggesting that HPA axis dysregulation might not represent a pathway by which catastrophizing heightens risk for development of persistent pain. It is possible that pain catastrophizing was not correlated with cortisol responses because the stimulus lacked personal significance for healthy participants.

Differential Involvement of Trigeminal Transition Zone and Laminated Subnucleus Caudalis in Orofacial Deep and Cutaneous Hyperalgesia: the Effects of Interleukin-10 and Glial Inhibitors

BackgroundIn addition to caudal subnucleus caudalis (Vc) of the spinal trigeminal complex, recent studies indicate that the subnuclei interpolaris/caudalis (Vi/Vc) transition zone plays a unique role in processing deep orofacial nociceptive input. Studies also suggest that glia and inflammatory cytokines contribute to the development of persistent pain. By systematically comparing the effects of microinjection of the antiinflammatory cytokine interleukin (IL)-10 and two glial inhibitors, fluorocitrate and minocycline, we tested the hypothesis that there was a differential involvement of Vi/Vc and caudal Vc structures in deep and cutaneous orofacial pain.ResultsDeep or cutaneous inflammatory hyperalgesia, assessed with von Frey filaments, was induced in rats by injecting complete Freund's adjuvant (CFA) into the masseter muscle or skin overlying the masseter, respectively. A unilateral injection of CFA into the masseter or skin induced ipsilateral hyperalgesia that started at 30 min, peaked at 1 d and lasted for 1-2 weeks. Secondary hyperalgesia on the contralateral site also developed in masseter-, but not skin-inflamed rats. Focal microinjection of IL-10 (0.006-1 ng), fluorocitrate (1 μg), and minocycline (0.1-1 μg) into the ventral Vi/Vc significantly attenuated masseter hyperalgesia bilaterally but without an effect on hyperalgesia after cutaneous inflammation. Injection of the same doses of these agents into the caudal Vc attenuated ipsilateral hyperalgesia after masseter and skin inflammation, but had no effect on contralateral hyperalgesia after masseter inflammation. Injection of CFA into the masseter produced significant increases in N-methyl-D-aspartate (NMDA) receptor NR1 serine 896 phosphorylation and glial fibrillary acidic protein (GFAP) levels, a marker of reactive astrocytes, in Vi/Vc and caudal Vc. In contrast, cutaneous inflammation only produced similar increases in the Vc.ConclusionThese results support the hypothesis that the Vi/Vc transition zone is involved in deep orofacial injury and suggest that glial inhibition and interruption of the cytokine cascade after inflammation may provide pain relief.

Sleep onset insomnia symptoms during hospitalization for major burn injury predict chronic pain

Both cross-sectional studies of chronic pain and sleep deprivation experiments suggest a bi-directional relationship between sleep and pain. Few longitudinal studies, however, have assessed whether acute insomnia following traumatic injury predicts the development of persistent pain. We sought to evaluate (1) whether in-hospital insomnia independently predicts long-term pain after burn injury and (2) whether in-hospital pain predicts future insomnia symptoms. We analyzed data on 333 subjects hospitalized for major burn injury (72.7% male; mean age = 41.1 ± 14.5 years) who were participating in the multi-site, Burn Model System project. Subjects completed measures of health, function (SF-36), and psychological distress (Brief Symptom Inventory) while in hospital, at 6, 12, and 24 months after discharge. Participants were categorized as either having or not having sleep onset insomnia at discharge. Linear mixed effects analyses revealed that persons reporting insomnia at discharge (40.5%) had significantly decreased improvement in pain and increased pain severity during long-term follow-up ( p < 0.001). More severe pain during the week preceding hospital discharge, time from injury, lack of college education and older age also contributed independent effects on chronic pain ( p < 0.05). In a reciprocal model ( N = 299), more severe pain during the week preceding discharge predicted increased rates of long-term sleep onset insomnia. In-hospital insomnia and pre-burn mental health symptoms were also highly significant predictors of insomnia. This study provides support for a long-term, prospective and reciprocal interaction between insomnia and pain. Future work should ascertain whether treatment of insomnia and pain during acute injury can prevent or minimize chronic pain.

TNF-α involves in altered prefrontal synaptic transmission in mice with persistent inflammatory pain

Tumor necrosis factor alpha (TNF-α) is implicated in the development of persistent pain. Its expression increases both spinally and supraspinally after peripheral inflammation. The anterior cingulate cortex (ACC) is a forebrain structure known for its roles in pain transmission and modulation. Prefrontal synaptic transmission is potentiated in mice with chronic pain through an enhancement of presynaptic transmitter release. However, it is not known if TNF-α expression is altered in the ACC in response to persistent pain and if synaptic transmission within this region is modulated by TNF-α. In the present study, we examined TNF-α expression in the mouse ACC following hind-paw administration of complete Freund's adjuvant (CFA) and examined the role of TNF-α in ACC synaptic transmission. Quantification of TNF-α at the protein level (by ELISA) revealed enhanced expression following CFA-induced peripheral inflammation. In vitro whole-cell patch-clamp recordings revealed that TNF-α significantly enhanced synaptic transmission through increased probability of neurotransmitter release in the ACC. Our findings provide evidence that presynaptic alterations caused by peripheral inflammation is partly attributable to the up-regulation of TNF-α in the ACC.

Calcium Calmodulin-Stimulated Adenylyl Cyclases Contribute to Activation of Extracellular Signal-Regulated Kinase in Spinal Dorsal Horn Neurons in Adult Rats and Mice

The extracellular signal-regulated kinase (Erk) cascades are suggested to contribute to excitatory synaptic plasticity in the CNS, including the spinal cord dorsal horn. However, many of their upstream signaling pathways remain to be investigated. Here, we demonstrate that glutamate and substance P (SP), two principal mediators of sensory information between primary afferent fibers and the spinal cord, activate Erk in dorsal horn neurons of both adult rat and mouse spinal cord. In genetic knock-out mice of calcium calmodulin-stimulated adenylyl cyclase subtypes 1 (AC1) and 8 (AC8), activation of Erk in dorsal horn neurons were significantly reduced or blocked, either after peripheral tissue inflammation or by glutamate or SP in spinal cord slices. Our studies suggest that AC1 and AC8 act upstream from Erk activation in spinal dorsal horn neurons and the calcium-AC1/AC8-dependent Erk signaling pathways may contribute to spinal sensitization, an underlying mechanism for the development of persistent pain after injury.

Supraspinal Brain-Derived Neurotrophic Factor Signaling: A Novel Mechanism for Descending Pain Facilitation

In the adult mammalian brain, brain-derived neurotrophic factor (BDNF) is critically involved in long-term synaptic plasticity. Here, we show that supraspinal BDNF-tyrosine kinase receptor B (TrkB) signaling contributes to pain facilitation. We show that BDNF-containing neurons in the periaqueductal gray (PAG), the central structure for pain modulation, project to and release BDNF in the rostral ventromedial medulla (RVM), a relay between the PAG and spinal cord. BDNF in PAG and TrkB phosphorylation in RVM neurons are upregulated after inflammation. Intra-RVM sequestration of BDNF and knockdown of TrkB by RNA interference attenuate inflammatory pain. Microinjection of BDNF (10-100 fmol) into the RVM facilitates nociception, which is dependent on NMDA receptors (NMDARs). In vitro studies with RVM slices show that BDNF induces tyrosine phosphorylation of the NMDAR NR2A subunit in RVM via a signal transduction cascade involving IP(3), PKC, and Src. The supraspinal BDNF-TrkB signaling represents a previously unknown mechanism underlying the development of persistent pain. Our findings also caution that application of BDNF for recovery from CNS disorders could lead to undesirable central pain.