Peripheral Pain Processing Research Articles

Pediatric Pain

ABSTRACT OBJECTIVE This article reviews pain disorders encountered in pediatric neurology practice and provides current information regarding the assessment and treatment of pediatric chronic pain. LATEST DEVELOPMENTS Data about pediatric pain management remain sparse, owing to a dearth of controlled trials and longitudinal studies in these patients. However, the field of pain management and understanding of central and peripheral pain processing has expanded to allow more effective treatment of a broad group of children and adolescents with pain associated with neurologic disease. Neuroimaging visualizes sensory and nonsensory systems, and genetic markers of sensitivity and disease may guide specific therapy. The concept of central sensitization in chronic pain disorders has supported the development of multidisciplinary paradigms for the comprehensive care of these patients. ESSENTIAL POINTS Pain involves sensory activation and central nervous system modulation in pediatric patients. Pediatric neurologists should be prepared to define, investigate, and treat pain disorders in this complex patient population. Appropriate interventions during childhood may attenuate or prevent chronic pain later in life. Current interventions include behavioral, physical, and pharmacologic approaches, as well as potential noninvasive tools for neuromodulation. Research is progressing in sensory measurement, neuroimaging, genetics, and neuroinflammation to guide future targeted therapies.

27042 Pressure-pain thresholds at baseline and in response to isometric exercise in Achilles tendinopathy

ABSTRACT IMPACT: Baseline presentation in AT (higher upper trapezius PPT with no difference at calf or tendon) may suggest a mechanism for persistent symptoms: with more advantageous central pain processing and no tradeoff peripherally, they may choose to continue their usual activities without regard for further damage to the affected tendon. OBJECTIVES/GOALS: Exercise-induced hypoalgesia, a reduction in pain with exercise, is often observed in healthy populations but is not well established in Achilles tendinopathy (AT). The aim was to compare pressure-pain threshold (PPT) at baseline and after fatiguing isometric exercise in AT and healthy controls. METHODS/STUDY POPULATION: 21 participants were recruited for the study: 7 AT (26.5 ±8.8 yrs), 14 control (22.1 ±3.2 yrs). After a familiarization session, participants completed an experimental session that involved performance of intermittent maximal voluntary isometric contractions (MVICs) (2s:2s duty cycle) in a Biodex3 dynamometer (Biodex Medical, Shirley, NY) for 4 minutes. PPT was measured at the medial gastrocnemius (calf), Achilles tendon, and upper trapezius at baseline and immediately following the fatiguing isometric task using a Somedic Algometer (Somedic AB, Sweden). Data are expressed as Mean(SD). Change in PPT is expressed as a percentage of baseline PPT. Units for PPT are kPa. A priori alpha was set to 0.05. RESULTS/ANTICIPATED RESULTS: There was no change in tendon or calf PPT following isometric exercise in AT (tendon: p=0.78; calf: p=0.76), while both increased (i.e., exercise-induced hypoalgesia) in controls (tendon: 9.5(17.8), p=0.03; calf: 21.3(22.7), p<0.01). Neither group experienced a post-exercise change in upper trapezius PPT (AT: p=0.35; control: p=0.37). There was no between-group difference in baseline calf (p=0.14) or tendon (p=0.19) PPT. However, baseline and post-exercise upper trapezius PPT were significantly higher in AT (baseline: 335.6(194.8); post-exercise: 321.2(170.1)) than in controls (baseline: 193.7(75.1), p<0.01; post-exercise: 198.1(79.1), p<0.01). DISCUSSION/SIGNIFICANCE OF FINDINGS: These findings suggest: (1) in persons with AT, central pain processing is altered at baseline, but unaffected in response to isometric fatiguing exercise; and (2) in persons with AT, peripheral pain processing is unaffected at baseline, but is altered in response to this mode and dosage of fatiguing isometric exercise.

Pain and Neuropathic Pain in Rheumatic Diseases

AbstractPain is a challenge to rheumatologists. Not only patients with active arthritis but also patients with a good therapeutic response and even in remission complain of persistent joint pain. It has been proposed that a chronic pain stimulus may have a greater impact in a chronic inflammatory state, and the process towards a pain condition may be influenced by individual predisposition for development of chronic pain. In addition, features of peripheral pain processing may be exacerbated by inflammation, and disturbed pain processing may be a feature contributing to widespread pain. Furthermore, a neuropathic component may be part of the total pain experience of our patients. There are many different strategies of pain therapy in patients with rheumatic diseases, such as pharmacological and non- pharmacological modalities.

Pressure pain thresholds in adults with patellofemoral pain and patellofemoral joint osteoarthritis: a case-control study.

Patellofemoral pain (PFP) and patellofemoral joint osteoarthritis (PFJOA) are common non-self-limiting conditions causing significant pain and disability. The underlying pain pathologies lack consensus with evidence suggesting reduced pressure pain thresholds (PPTs) in adolescent females with PFP and individuals with knee osteoarthritis. A paucity of evidence exists for mixed-sex adults with PFP and PFJOA in isolation. Exploring if pain sensitisation is a dominant feature of PFP and PFJOA may have important implications for the delivery of a patient centred management approach. The primary aim was to measure local and remote PPTs in PFP and PFJOA patients compared to matched controls. Secondary aims were to evaluate the relationship between PPTs and (1) condition severity and (2) knee function. 13 PFP patients plus 20 matched controls and 15 PFJOA patients plus 34 matched controls were recruited from a UK mixed-sex adult population. Controls were matched on age, sex and activity level. Demographic details, Tegner activity level score, symptom duration, condition severity (Kujala and KOOS-PF scores for PFP and PFJOA, respectively) and knee function (Modified Whatman score rating of five single leg squats) were recorded. PPTs were measured at six sites: five local around the knee, one remote on the contralateral leg. Between-group differences were tested using a two-way mixed model analysis of variance with repeated measures. Strength of association between PPTs and condition severity and knee function were tested using Spearman's rank order correlation. No statistically significant difference in PPTs were observed between the PFP patients [F(1,31) = 0.687, p = 0.413, η2 = 0.022] or PFJOA patients [F(1,47) = 0.237, p = 0.629, η2 = 0.005] and controls. Furthermore, no correlation was found between PPTs and condition severity or knee function in PFP or PFJOA (p > 0.05). Results suggest mechanical pain sensitisation is not a dominant feature of UK mixed-sex adults with PFP or PFJOA. PFP and PFJOA remain persistent pain complaints which may not be well explained by objective measures of sensitivity such as PPTs. The findings suggest that peripheral pain processing changes leading to pain sensitisation is not a key feature in PFP or PFJOA. Instead the underlying pain pathway is likely to remain primary nociceptive, possibly with a subgroup of patients who experience pain sensitisation and might benefit from a more targeted management approach.

Common Missense Variant of SCN9A Gene Is Associated with Pain Intensity in Patients with Chronic Pain from Disc Herniation.

Lumbar intervertebral disk herniation (LDH) is considered one of the major risk factors for lower back pain, mainly caused by irritation of a spinal nerve or its root. One of the genes related to pain perception is SCN9A, which encodes the voltage gated sodium channel NaV1.7, a key molecule involved in peripheral pain processing. It had been presented before that a common polymorphism within SCN9A (rs6746030: G > A, R1150W) might influence nociception in the general population. Hence, the present study was aimed at investigating the association between SCN9A polymorphism and pain sensitivity. Pain intensity was measured by means of the visual analog pain scale (VAS) in 176 Caucasian patients with a history of leg and back pain who had been diagnosed with LDH and underwent lumbar discectomy. SCN9A polymorphism was determined by means of TaqMan assay. A significantly higher preoperative back pain intensity was observed among rs6746030 A minor allele carriers, compared with GG homozygotes (VAS = 7.5 ± 2.4 vs 6.5 ± 2.7, P = 0.012). Similarly, A allele carriers were characterized by higher values of leg pain prior to surgery (VAS = 7.8 ± 2.3 vs 6.8 ± 2.6, P = 0.013). However, postoperative improvement in pain reduction was similar in both groups. Our results suggest that the SCN9A rs6746030 polymorphism may be associated with pain intensity in patients suffering from symptomatic disc herniation.

Update on Treatment Guideline in Fibromyalgia Syndrome with Focus on Pharmacology.

Fibromyalgia syndrome (FMS) is a chronic condition with unknown aetiology. The pathophysiology of the disease is incompletely understood; despite advances in our knowledge with regards to abnormal central and peripheral pain processing, and hypothalamo–pituitary–adrenal dysfunction, there is no clear specific pathophysiological therapeutic target. The management of this complex condition has thus perplexed the medical community for many years, and several national and international guidelines have aimed to address this complexity. The most recent guidelines from European League Against Rheumatism (EULAR) (2016), Canadian Pain Society (2012), and The Association of the Scientific Medical Societies in Germany (AWMF) (2012) highlight the change in attitudes regarding the overall approach to FMS, but offer varying advice with regards to the use of pharmacological agents. Amitriptyline, Pregabalin and Duloxetine are used most commonly in FMS and though modestly effective, are useful adjunctive treatment to non-pharmaceutical measures.

Oxidation differentially modulates the recombinant voltage-gated Na+ channel α-subunits Nav1.7 and Nav1.8

Voltage-gated Na+ channels regulate neuronal excitability by generating the upstroke of action potentials. The α-subunits Nav1.7 and Nav1.8 are required for normal function of sensory neurons and thus for peripheral pain processing, but also for an increased excitability leading to an increased pain sensitivity under several conditions associated with oxidative stress. While little is known about the direct effects of oxidants on Nav1.7 and Nav1.8, a recent study on mouse dorsal root ganglion neurons suggested that oxidant-induced alterations of nociceptor excitability are primarily driven by Nav1.8. Here we performed whole-cell patch clamp recordings to explore how oxidation modulates functional properties of recombinant Nav1.7 and Nav1.8 channels. The strong oxidant chloramine-T (ChT) at 100 and 500µM induced a shift of the voltage-dependency of activation towards more hyperpolarized potentials. While fast inactivation was stabilized by 100µM ChT, it was partially removed by 500µM ChT on both α-subunits (Nav1.7<Nav1.8) and enabled them to produce large non-inactivating persistent currents as well as prominent ramp currents. Slow inactivation of both peak and persistent currents for both Nav1.7 and Nav1.8 were stabilized by ChT. Our data demonstrate that oxidation promotes gating of Nav1.7 and Nav1.8 by reducing the threshold for activation and by abrogating fast inactivation. The resulting persistent currents are regulated by slow inactivation and appear to be more prominent for Nav1.8 as compared to Nav1.7.

(507) Effects of light brushing on peripheral and central pain processing of pain in patients with Fibromyalgia

Central sensitization plays a role in the persistence, amplification, and spread of pain in patients with Fibromyalgia Syndrome (FMS). Graston Technique (GT) involves instrument-assisted soft tissue mobilization based on the concepts of manual therapy and cross friction massage. Light Brushing (LB) stroke is proposed to desensitize the treatment area prior to more aggressive stages of the GT protocol. The efficacy of LB in FMS has not been determined. The present study investigated changes in measures of central and peripheral pain processing following LB in patients with FMS and healthy controls (HCs).

Sodium channelopathies and pain

Chronic pain often represents a severe, debilitating condition. Up to 10% of the worldwide population are affected, and many patients are poorly responsive to current treatment strategies. Nociceptors detect noxious conditions to produce the sensation of pain, and this signal is conveyed to the CNS by means of action potentials. The fast upstroke of action potentials is mediated by voltage-gated sodium channels, of which nine pore-forming alpha-subunits (Nav1.1-1.9) have been identified. Heterogeneous functional properties and distinct expression patterns denote specialized functions of each subunit. The Nav1.7 and Nav1.8 subunits have emerged as key molecules involved in peripheral pain processing and in the development of an increased pain sensitivity associated with inflammation and tissue injury. Several mutations in the SCN9A gene encoding for Nav1.7 have been identified as important cellular substrates for different heritable pain syndromes. This review aims to cover recent progress on our understanding of how biophysical properties of mutant Nav1.7 translate into an aberrant electrogenesis of nociceptors. We also recapitulate the role of Nav1.8 for peripheral pain processing and of additional sodium channelopathies which have been linked to disorders with pain as a significant component.

The Relationship Between Pain Perception and Interoception

The question of whether the perception of externally applied pain stimuli and the perception of interoceptive stimuli are based upon similar neuronal or behavioral processes is still open to debate. If such a similarity exists, one would expect that persons who are highly sensitive to visceral stimuli would also exhibit a higher sensitivity to pain stimuli. The present study investigated the sensitivity to heat pain of individuals with high vs. low cardiac interoceptive sensitivity. Pain threshold and pain tolerance were assessed using a testing-the-limits procedure. Furthermore, participants rated the subjective intensity and unpleasantness of tonic heat stimuli on visual analog scales and in a questionnaire. The results show that pain experience did not differ between participants with high and low interoceptive sensitivity, nor did correlation analyses reveal significant relationships between pain experience and cardiac interoceptive sensitivity. These findings suggest that the pathway of peripheral pain processing is at least partially independent of the pathway of interoceptive sensations.

Fibromyalgia: A Unifying Neuroendocrinologic Model for Understanding Its Pathophysiology

AbstractFibromyalgia is believed to affect at least 2% of the population. Despite advances in the scientific understanding of the derangements of central and peripheral pain processing mechanisms in fibromyalgia, no current models of its pathophysiology account for the other clinical conditions associated with it such as fatigue, migraine headache, irritable bowel syndrome, and sleep cycle abnormalities. A neuroendocrinologic model of fibromyalgia is presented that accommodates both its known central and peripheral pain mechanisms as well as the myriad of hormonal, visceral, and psychological symptoms associated with that disorder. This model also provides a unifying pathophysiologic basis of fibromyalgia and chronic muscle pain, and offers the potential for developing new avenues of research and treatment for these enigmatic, frequently disabling medical conditions.

Ultraviolet-B induced inflammation of human skin: Characterisation and comparison with traditional models of hyperlagesia

The effect on human skin of over-exposure to solar ultraviolet radiation (UVR) has been well described. The erythema produced is commonly referred to as ‘sunburn’. Recently UVR induced inflammation has been utilised as a human model of sub-acute pain. Our aim was to characterise the sensory phenotype of UVB inflammation in human volunteers. We delivered UVB to small areas of volar forearm skin in healthy volunteers and found that the degree of inflammation and concomitant increase in sensitivity to cutaneous stimuli were UVB dose and time dependant. We directly compared UVB induced inflammation and the more established thermal burn and topical capsaicin pain models. UVB inflammation produced precisely demarcated erythematous lesions without secondary flare. Both thermal burns and topical capsaicin produced large areas of flare, indistinguishable in character from the primary lesions. Moreover, UVB inflammation induced large reductions in mechanical pain threshold restricted to the primary lesion site, whereas the more established inflammatory pain models produced not only primary hypersensitivity but also significant areas of secondary mechanical hypersensitivity. Taken together these findings suggest that UVB inflammation, at least using moderate doses produces sensory changes primarily by sensitising peripheral pain processing in the relative absence of alterations in central pain processing.

Contribution of transient receptor potential vanilloid subfamily 1 to endothelin-1-induced thermal hyperalgesia

Endothelin-1 (ET-1) plays an important role in peripheral pain processing. However, the mechanisms of the nociceptive action of ET-1 have not been fully elucidated. In this study, we investigated the contribution of transient receptor potential vanilloid subfamily 1 (TRPV1) to ET-1-induced thermal hyperalgesia. Intraplantar ET-1-induced thermal hyperalgesia was examined by assessing the paw withdrawal latency to noxious heat stimuli. In electrophysiological study, whole-cell patch-clamp recordings were performed to investigate the interaction of ET-1 and TRPV1 using human embryonic kidney 293 (HEK293) cells expressing endothelin type A receptor (ET A) and TRPV1. Intraplantar ET-1 (3, 10 and 30 pmol) produced thermal hyperalgesia in a dose-dependent manner. Thermal hyperalgesia was attenuated by the inhibition of ET A and protein kinase C (PKC) but not that of ET B. ET-1-induced thermal hyperalgesia was significantly attenuated in TRPV1-deficient mice compared with that in wild-type mice. In voltage-clamp experiments, 10 nM capsaicin evoked small inward currents in HEK293 cells expressing TRPV1 and ET A. In the presence of ET-1, capsaicin produced much larger current responses ( P<0.05). Mutation at PKC-specific TRPV1 phosphorylation sites (S800A/S502A) and PKC inhibitors inhibited the potentiating effect of ET-1. In addition, ET-1 decreased the temperature threshold for TRPV1 activation in a PKC-dependent manner (from 41.0±0.4 °C to 32.6±0.6 °C). In addition, Western blot analysis was also performed to confirm ET-1-induced phosphorylation of TRPV1. Incubation of ET-1 and intraplantar ET-1 evoked phosphorylation of TRPV1 in HEK293 cells expressing TRPV1 and ET A and the skin, respectively. These results suggest that the sensitization of TRPV1 activity through an ET A-PKC pathway contributes to ET-1-induced thermal hyperalgesia.