Development Of Persistent Pain Research Articles

Reduced sleep, stress responsivity, and female sex contribute to persistent inflammation-induced mechanical hypersensitivity in rats

Studies in humans suggest that female sex, reduced sleep opportunities and biological stress responsivity increase risk for developing persistent pain conditions. To investigate the relative contribution of these three factors to persistent pain, we employed the Sciatic Inflammatory Neuritis (SIN) model of repeated left sciatic perineurial exposures to zymosan, an inflammatory stimulus, to determine their impact upon the development of persistent mechanical hypersensitivity. Following an initial moderate insult, a very low zymosan dose was infused daily for eight days to model a sub-threshold inflammatory perturbation to which only susceptible animals would manifest or maintain mechanical hypersensitivity. Using Sprague Dawley rats, maintaining wakefulness throughout the first one-half of the 12-h light phase resulted in a bilateral reduction in paw withdrawal thresholds (PWTs); zymosan infusion reduced ipsilateral PWTs in all animals and contralateral PWTs only in females. This sex difference was validated in Fischer 344, Lewis and Sprague Dawley rats, suggesting that females are the more susceptible phenotype for both local and centrally driven responses to repeated low-level inflammatory perturbations. Hypothalamic-pituitary-adrenal (HPA) axis hyporesponsive Lewis rats exhibited the most robust development of mechanical hypersensitivity and HPA axis hyperresponsive Fischer 344 rats matched the Lewis rats' mechanical hypersensitivity throughout the latter four days of the protocol. If HPA axis phenotype does indeed influence these findings, the more balanced responsivity of Sprague Dawley rats would seem to promote resilience in this paradigm. Taken together, these findings are consistent with what is known regarding persistent pain development in humans.

Cortical reorganization after macroreplantation at the upper extremity: a magnetoencephalographic study

With the development of microsurgical techniques, replantation has become a feasible alternative to stump treatment after the amputation of an extremity. It is known that amputation often induces phantom limb pain and cortical reorganization within the corresponding somatosensory areas. However, whether replantation reduces the risk of comparable persisting pain phenomena as well as reorganization of the primary somatosensory cortex is still widely unknown. Therefore, the present study aimed to investigate the potential development of persistent pain and cortical reorganization of the hand and lip areas within the sensory cortex by means of magnetoencephalographic dipole analyses after replantation of a traumatically amputated upper limb proximal to the radiocarpal joint. Cortical reorganization was investigated in 13 patients with limb replantation using air puff stimulation of the phalanges of both thumbs and both corners of the lower lip. Displacement of the centre of gravity of lip and thumb representations and increased cortical activity were found in the limb and face areas of the primary somatosensory cortex contralateral to the replanted arm when compared to the ipsilateral hemisphere. Thus, cortical reorganization in the primary somatosensory cortex also occurs after replantation of the upper extremity. Patients' reports of pain in the replanted body part were negatively correlated with the amount of cortical reorganization, i.e. the more pain the patients reported, the less reorganization of the subjects' hand representation within the primary somatosensory cortex was observed. Longitudinal studies in patients after macroreplantation are necessary to assess whether the observed reorganization in the primary somatosensory cortex is a result of changes within the representation of the replanted arm and/or neighbouring representations and to assess the relationship between the development of persistent pain and reorganization.

Spinal 5-HT3 receptors mediate descending facilitation and contribute to behavioral hypersensitivity via a reciprocal neuron-glial signaling cascade.

BackgroundIt has been recently recognized that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT3 receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT3 receptor and its contribution to facilitation of pain remain unclear.ResultsIn the present study, activation of spinal 5-HT3 receptors by intrathecal injection of a selective 5-HT3 receptor agonist SR 57227 induced spinal glial hyperactivity, neuronal hyperexcitability and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via the chemokine fractalkine, microglia to astrocyte signaling via cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of NMDA receptors in the spinal dorsal horn. Glial hyperactivation in spinal dorsal horn after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference.ConclusionsThese findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neurons and glia.

Complex Multilocus Effects of Catechol-O-Methyltransferase Haplotypes Predict Pain and Pain Interference 6 Weeks After Motor Vehicle Collision

Catechol-O-methyltransferase, encoded by COMT gene, is the primary enzyme that metabolizes catecholamines. COMT haplotypes have been associated with vulnerability to persistent non-traumatic pain. In this prospective observational study, we investigated the influence of COMT on persistent pain and pain interference with life functions after motor vehicle collision (MVC) in 859 European American adults for whom overall pain (0-10 numeric rating scale) and pain interference (Brief Pain Inventory) were assessed at week 6 after MVC. Ten single nucleotide polymorphisms spanning the COMT gene were successfully genotyped, and nine were present in three haploblocks: block 1 (rs2020917, rs737865, rs1544325), block 2 (rs4633, rs4818, rs4680, rs165774), and block 3 (rs174697, rs165599). After adjustment for multiple comparisons, haplotype TCG from block 1 predicted decreased pain interference (p=0.004). The pain-protective effect of the low pain sensitivity (CGGG) haplotype from block 2 was only observed if at least one TCG haplotype was present in block 1 (haplotype×haplotype interaction p=0.002 and <0.0001 for pain and pain interference, respectively). Haplotype AG from block 3 was associated with pain and interference in males only (sex×haplotype interaction p=0.005 and 0.0005, respectively). These results suggest that genetic variants in the distal promoter are important contributors to the development of persistent pain after MVC, directly and via the interaction with haplotypes in the coding region of the gene.

Chronic pain after childbirth

Although childbirth is considered a natural event, some deliveries may necessitate instrumentation or surgical intervention. In contrast with trauma or surgery, persistent pain after delivery has received little attention until recently, despite the large number of individuals potentially at risk. Excluding pre-existing pain or pain that developed during pregnancy, prospective studies show a surprisingly low prevalence of persistent pain after childbirth, much lower than the prevalence reported in retrospective studies and that of persistent postsurgical pain in a general population for similar procedures. The nature of persistent pain itself remains poorly characterized; the chronic pain following caesarean delivery appears to be predominantly neuropathic, but the intensity is generally lower than usually reported for other types of chronic neuropathic pain. Finally, the type of delivery and the degree of tissue trauma do not seem to impact the risk of developing persistent pain. It is unclear whether individual factors place specific women at a risk for persistent pain. Experimental study suggests that protective mechanisms against the development of neuropathic pain may be active during the puerperium, but whether these mechanisms exist following human childbirth remains unknown. Some recent findings on the development of persistent pain after childbirth are intriguing and might open the way to interesting perspectives for the treatment of persistent pain caused by trauma or surgery.

A Potential Role for Substance P and Interleukin‐6 in the Cerebrospinal Fluid of Cavalier King Charles Spaniels with Neuropathic Pain

Neuropathic pain can be a clinical sign in Cavalier King Charles Spaniels (CKCS) with syringomyelia. The pathophysiology of this pain is not fully understood. Neuropathic pain in CKCS is a result of a neuroinflammatory process. Twenty-six client-owned dogs: 15 dogs with clinical signs of cervical hyperesthesia (group 1), and 11 dogs without of clinical signs (group 2). Dogs were examined by magnetic resonance imaging (MRI). Interleukin-6, tumor necrosis factor alpha, and substance P were measured in CSF and compared with morphological findings on MRI and clinical pain scores. All dogs without clinical signs had symmetrical syringomyelia, whereas in the group with pain, 6 dogs had symmetrical and 9 dogs had asymmetrical syringomyelia. Pain and syringomyelia asymmetry were correlated, and a strong association between pain and dorsal horn involvement of syringomyelia was observed. There was no significant difference between the mean width of the syringomyelia in dogs with or without pain. The concentrations of interleukin-6 and substance P were significantly higher in dogs with neuropathic pain. Tumor necrosis factor alpha was not detected in either group. Concentrations of substance P were significantly higher in dogs with asymmetrical syringomyelia or dorsal horn involvement, whereas interleukin-6 concentrations were not significantly different between groups. Release of interleukin-6 and substance P may initiate proinflammatory effects leading to development of persistent pain in CKCSs with syringomyelia.

Persistent pain and sensory disturbances after treatment for breast cancer: six year nationwide follow-up study

Objective To examine the development of persistent pain after treatment for breast cancer and to examine risk factors associated with continuing pain. Design Repeated cross sectional study in a previously...

Postoperative opioids

Postoperative opioids

Epigenetics and the Transition from Acute to Chronic Pain

The objective of this study was to review the epigenetic modifications involved in the transition from acute to chronic pain and to identify potential targets for the development of novel, individualized pain therapeutics. Epigenetics is the study of heritable modifications in gene expression and phenotype that do not require a change in genetic sequence to manifest their effects. Environmental toxins, medications, diet, and psychological stresses can alter epigenetic processes such as DNA methylation, histone acetylation, and RNA interference. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, steroid responsiveness, and opioid sensitivity, they are likely key factors in the development of chronic pain. Although our knowledge of the human genetic code and disease-associated polymorphisms has grown significantly in the past decade, we have not yet been able to elucidate the mechanisms that lead to the development of persistent pain after nerve injury or surgery. This is a focused literature review of epigenetic science and its relationship to chronic pain. Significant laboratory and clinical data support the notion that epigenetic modifications are affected by the environment and lead to differential gene expression. Similar to mechanisms involved in the development of cancer, neurodegenerative disease, and inflammatory disorders, the literature endorses an important potential role for epigenetics in chronic pain. Epigenetic analysis may identify mechanisms critical to the development of chronic pain after injury, and may provide new pathways and target mechanisms for future drug development and individualized medicine.

Intraoperative nerve identification and chronic postherniorrhaphy pain

First of all, we thank Drs. Chen and Amid [1] for their very thoughtful comments and update on the role of intraoperative nerve identification during groin hernia repair and the risk of development of chronic pain. We agree with all their comments, except that our conclusions in the abstract does not ‘‘conclude that nerve identification does not decrease rates of pain in routine practice’’ as quoted, but rather that ‘‘although intraoperative inguinal nerve identification should be aimed at, other factors may contribute to the risk of nerve damage and persistent pain after open groin hernia repair’’ [2]. This conclusion supports the comments by Chen and Amid [1], despite that we in the present study were not able to demonstrate any influence of nerve identification on signs of nerve damage or on development of persistent pain. The discussion on identification of the ‘‘genitofemoral nerve’’ (which we entirely agree should be named ‘‘genital branch’’) is to some extent semantic as we agree that routine direct identification should not be done, but only if necessary for the herniotomy per se. This may explain our low identification rate of the genital branch (21.3 %) which, interestingly, is within the same range as reported from a recent hernia specialist publication on persistent pain problems, with an identification rate of 26.5 % [3]. Also, we agree that the use of heavy-weight mesh may have contributed to the pain problems, but when the study was conducted there was little conclusive evidence for differences between mesh type and persistent pain. In summary, the valuable comment by Drs. Chen and Amid provides a sound balance on this important (but also difficult) topic of persistent postherniorrhaphy pain compared to our rather negative findings [1]. We entirely support their conclusion that surgical technique is a crucial component to reduce this disturbing problem.

Astrocytic Signaling in Persistent Pain

Functional sensitization and structural plasticity in the nociceptive pathways and modulatory networks in the peripheral and central nervous system develop following tissue and nerve injury and result in persistent or chronic pain, a major challenge to clinical management. Development of novel analgesic drugs requires a better understanding of the molecular and cellular mechanisms underlying persistent pain. Research during the last three decades has focused on the involvement of neuronal mechanisms in persistent pain. Recently accumulating evidence indicates that reactive glial cells play a critical role in peripheral and central sensitization during the development of persistent pain in variety of animal pain models. The purpose of this review is to highlight important recent advances in astrocytic mechanisms in experimentally persistent pain and the potential to use this information to develop new drugs targeting astrocytic signaling in the treatment of pathological pain. Keywords: Astrocyte, signal transduction, proinflammatory cytokines, neronal plasticity, pain, analgesic drugs, tissue injury, astrocytic signaling, CNS, peripheral sensitization

Spinal 5-HT3Receptor Activation Induces Behavioral Hypersensitivity via a Neuronal-Glial-Neuronal Signaling Cascade

Recent studies indicate that the descending serotonin (5-HT) system from the rostral ventromedial medulla (RVM) in the brainstem and the 5-HT(3) receptor subtype in the spinal dorsal horn are involved in enhanced descending pain facilitation after tissue and nerve injury. However, the mechanisms underlying the activation of the 5-HT(3) receptor and its contribution to facilitation of pain remain unclear. In the present study, activation of spinal 5-HT(3) receptor by intrathecal injection of a selective 5-HT(3) receptor agonist, SR57227, induced spinal glial hyperactivity, neuronal hyperexcitability, and pain hypersensitivity in rats. We found that there was neuron-to-microglia signaling via chemokine fractalkine, microglia to astrocyte signaling via the cytokine IL-18, astrocyte to neuronal signaling by IL-1β, and enhanced activation of GluN (NMDA) receptors in the spinal dorsal horn. In addition, exogenous brain-derived neurotrophic factor-induced descending pain facilitation was accompanied by upregulation of CD11b and GFAP expression in the spinal dorsal horn after microinjection in the RVM, and these events were significantly prevented by functional blockade of spinal 5-HT(3) receptors. Enhanced expression of spinal CD11b and GFAP after hindpaw inflammation was also attenuated by molecular depletion of the descending 5-HT system by intra-RVM Tph-2 shRNA interference. Thus, these findings offer new insights into the cellular and molecular mechanisms at the spinal level responsible for descending 5-HT-mediated pain facilitation during the development of persistent pain after tissue and nerve injury. New pain therapies should focus on prime targets of descending facilitation-induced glial involvement, and in particular the blocking of intercellular signaling transduction between neuron and glia.

Persistent pain after mastectomy with reconstruction

Study Objective To determine the prevalence of persistent postsurgical pain (PPSP) and its influence on functional status, and to examine associations between PPSP and single nucleotide polymorphisms of the catechol-O-methyltransferase (COMT) gene and the guanosine triphosphate cyclohydrolase 1 (GCH1) gene following mastectomy and reconstruction. Design Retrospective study. Setting Two teaching hospitals. Patients From the population of women who had undergone breast reconstruction following mastectomy for breast cancer over a 6-year period, 42 women agreed to participate in the assessment (55.3% of the total sample). Interventions The Rand 36-Item Health Survey 1.0, the Patient-Specific Functional Scale, the McGill Pain Questionnaire (long form), visual analog scales for anxiety and pain, and the Hospital Anxiety and Depression Scale were administered. Blood was taken for genetic analysis. Quantitative sensory testing was performed using a standard electrical stimulus. Measurements Surgical procedures, perioperative analgesic requirements, pain scores, and adjuvant therapies were noted. Height, weight, menstrual status, and arm circumference also were recorded. Main Results 42 (55.3%) patients took part in the assessment, and 18 (43%) reported PPSP. Those with PPSP achieved lower scores on the Patient-Specific Functional Scale ( P = 0.040) and had been given more morphine perioperatively. A trend was noted between occurrence of PPSP and the val158met polymorphism of the COMT gene ( P = 0.06). Conclusions Persistent pain after mastectomy and breast reconstruction has a high prevalence (43%). Genetic mutations may contribute to the development of persistent pain following surgery; however, larger studies are required for confirmation.

Chronic pain after hip and knee replacement

Chronic pain after hip and knee replacement is a prevalent and overlooked issue to be addressed in the health care industry. Patients seek out joint replacements to relieve their chronic pain and restore their functional activities because of arthritis and injury. The intensity and duration of postsurgical pain vary, but with uncomplicated wound healing, the pain typically shows progressive attenuation. Chronic pain after surgery occurs after the normal time for tissue to heal and can be detrimental for the patient. It is possible that certain nerve damage or irritation during surgery plays a role in development of persistent pain after joint replacement. The nature and properties of persistent postsurgical pain are poorly characterized. Risk factors for persistent postsurgical pain after these surgeries are vast and inclusive of preoperative, intraoperative, and postoperative factors in relation to pain catastrophizing, surgical approach, nerve injury, and acute pain management. Pain catastrophizing is conceptualized as a negative cognitive–affective response to anticipated or actual pain and has been associated with many important pain-related outcomes. The majority of the times the views of medical and surgical interventions differ from the surgeons and the patients, especially in respect to the assessment of function and pain. Patient-reported outcome tools and assessment of satisfaction are included to ensure the patient's perception of the end results is included in the evaluation of total knee replacement.

Impact of Psychological Factors in the Experience of Pain

This article reviews the role of psychological factors in the development of persistent pain and disability, with a focus on how basic psychological processes have been incorporated into theoretical models that have implications for physical therapy. To this end, the key psychological factors associated with the experience of pain are summarized, and an overview of how they have been integrated into the major models of pain and disability in the scientific literature is presented. Pain has clear emotional and behavioral consequences that influence the development of persistent problems and the outcome of treatment. Yet, these psychological factors are not routinely assessed in physical therapy clinics, nor are they sufficiently utilized to enhance treatment. Based on a review of the scientific evidence, a set of 10 principles that have likely implications for clinical practice is offered. Because psychological processes have an influence on both the experience of pain and the treatment outcome, the integration of psychological principles into physical therapy treatment would seem to have potential to enhance outcomes.

Analysis of hyperalgesia time courses in humans after painful electrical high-frequency stimulation identifies a possible transition from early to late LTP-like pain plasticity

Electrical high-frequency stimulation (HFS) of skin afferents elicits long-term potentiation (LTP)-like hyperalgesia in humans. Time courses were evaluated in the facilitating (homotopic) or facilitated (heterotopic) pathways to delineate the relative contributions of early or late LTP-like pain plasticity. HFS in healthy subjects (n=55) elicited highly significant pain increases to electrical stimuli via the conditioning electrode (to 145% of control, homotopic pain LTP) and to pinprick stimuli in adjacent skin (to 190% of control, secondary hyperalgesia). Individual time courses in subjects expressing a sufficient magnitude of hyperalgesia (>20% pain increase, n=28) revealed similar half-lives of homotopic pain LTP and secondary hyperalgesia of 6.9h and 4.9h (log10 mean 0.839±0.395 and 0.687±0.306) and times to full recovery of 48h and 24h (log10 mean 1.679±0.790 and 1.373±0.611). Time course and peak magnitudes were not correlated between (r=−0.19to+0.21, NS), nor within both readout (r=0.29 and 0.31, NS). In most subjects, time courses were consistent with early LTP1. Notably, in some subjects (10 of 28), estimated times to full recovery were much longer (>10days), possibly indicating development of late LTP2-like pain plasticity. Dynamic mechanical allodynia (only present in 16 of 55 subjects) lasted for a shorter time than secondary hyperalgesia. Three different readouts of nociceptive central sensitization suggest that brief intense nociceptive input elicits early LTP1 of pain sensation (based on posttranslational modifications), but susceptible subjects may already develop longer-lasting late LTP2 (based on transcriptional modifications). These findings support the hypothesis that LTP may contribute to the development of persistent pain disorders.Homotopic pain LTP, secondary hyperalgesia, and dynamic mechanical allodynia after painful electrical high-frequency stimulation are mostly LTP1-like processes terminating within hours/1day, but susceptible subjects may exhibit LTP2-like pain plasticity lasting many days or weeks.

Perioperative pain management after thoracotomy

Perioperative acute pain and the development of persistent pain after thoracotomy are major problems severely affecting health-related quality of life. This review examines and highlights recent strategies and advances in perioperative pain management in this field. Despite the fact that thoracic epidural analgesia (TEA) is considered the 'gold standard' of perioperative care after thoracotomy, other local and regional techniques have emerged within recent years and seem to become valid alternatives to TEA. The use of continuous paravertebral blockade, in particular, may provide similar analgesia and fewer adverse effects than TEA. Multimodal systemic approaches, including the use of ketamine and gabapentinoids are being investigated as well as the effect of surgical techniques and adjuvant therapies such as transcutaneous electrical nerve stimulation on post-thoracotomy pain. Even though thoracotomy is associated with significant postoperative complications, a growing understanding of the underlying pathophysiology and advances in multimodal pain therapy concepts in this specific group of patients are promising improved postoperative outcomes and potential reduction of the incidence of persistent pain.

Atypical Focal Osteomyelitis as Initial Manifestation of AIDS

Persistent pain development after a skeletal contusion rarely poses the diagnosis of osteomyelitis. We report the case of a fibular head contusion as an initial manifestation of a focal abscess development in a healthy young patient. The traditional treatment of surgical drainage revealed the presence of an atypical Mycobacterium haemophilum isolates in the abscess. This lead to further investigations that concluded and established the diagnosis of AIDS. Conclusion. Isolation of an atypical Mycobacterium haemophilum in any abscess should lead the physician to accomplish further investigations and look for AIDS even in young healthy subjects.

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.