VGF: a biomarker and potential target for the treatment of neuropathic pain? Neuropathic pain (NP) remains an area of considerable unmet medical need. A persistent challenge in the management of NP is to target the specific mechanisms leading to a change from normal to abnormal sensory perception while ensuring that the defensive pain perception remains intact. Targeting VGF-derived neuropeptides may offer this opportunity. VGF was first identified in 1985 and is highly expressed after nerve injury and inflammation in neurons of both the peripheral and central nervous system. Subsequent studies implicate the vgf gene and its products in pain pathways. This narrative review was supported by a systematic search to identify, select, and critically appraise all relevant research investigating the role of VGF-derived neuropeptides in pain pathways. It predominantly focuses on in vivo investigations of the role of VGF in the initiation and maintenance of NP. VGF expression levels are very low under normal physiological conditions and nerve injury results in rapid and robust upregulation, increasing mechanical and thermal hypersensitivity. The identification of the 2 complement receptors with which VGF neuropeptides interact suggests a novel interplay of neuronal and immune signalling mediators. The understanding of the molecular mechanisms and signalling events by which VGF-derived active neuropeptides exert their physiological actions is in its infancy. Future work should aim to improve understanding of the downstream consequences of VGF neuropeptides thereby providing novel insights into pain mechanisms potentially leading to the identification of novel therapeutic targets. Corresponding author. Address: Pain Research, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, Chelsea, Westminster Hospital Campus, 369 Fulham Rd, London SW10 9NH, United Kingdom. Tel.: +44 (0) 20 87468424. E-mail address: n.soliman16@imperial.ac.uk (N. Soliman). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painrpts.com). Received March 20, 2019 Received in revised form July 12, 2019 Accepted August 08, 2019 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Prioritizing a sequence of short-duration groups as the standardized pathway for chronic noncancer pain at an Australian tertiary multidisciplinary pain service: preliminary outcomes Objective: To describe implementation and report preliminary outcomes of a resource-efficient, standardized group pathway for chronic noncancer pain. Design: Descriptive cross-sectional study of a group-based pain management pathway in comparison with an Australasian benchmarking data set. Setting: An Australian tertiary multidisciplinary pain service. Subjects: Patients with chronic noncancer pain actively participating in the group pathway in 2016. Methods: Referred patients were prioritized to a short-duration group–based standardized pain management pathway linking education, assessment, and treatment groups. Measures of pain, mood, self-efficacy, and catastrophizing and reduction in daily opioid use were collated from the Australasian data set. Results: In 2016, 928 patients were actively engaged with the pain service. More patients were prioritized to receive treatment in a group format in comparison with other Australasian services (68.4% vs 22%). A greater percentage of patients attended their first clinical contact within 3 months of referral (81.4%) compared with the Australasian average (68.6%). Comparable improvements in average pain intensity, pain interference, depression, anxiety, stress, pain catastrophizing, and self-efficacy were observed. There was significantly greater reduction in opioid use, including for those taking more than 40 mg of oral morphine equivalent daily dose. Conclusion: Implementation of a sequence of short-duration groups as the default clinical pathway resulted in shorter waiting times and noninferior outcomes in key areas for patients completing the program, compared with Australasian averages. Given the resource efficiencies of the group process, this finding has implications for service design. Corresponding author. Address: Hunter Integrated Pain Service, Locked Bag 1, Hunter Region Mail Center, Newcastle, New South Wales 2310, Australia. Tel.: +61249223435; fax: +61249855045. E-mail address: hema.rajappa@health.nsw.gov.au (H. Rajappa). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painrpts.com). Received May 28, 2019 Received in revised form July 16, 2019 Accepted July 22, 2019 This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike License 4.0 (CC BY-NC-SA) which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Unpredictable stress delays recovery from exercise-induced muscle pain: contribution of the sympathoadrenal axis Introduction: Although stress is a well-establish risk factor for the development of chronic musculoskeletal pain, the underlying mechanisms, specifically the contribution of neuroendocrine stress axes, remain poorly understood. Objective: To evaluate the hypothesis that psychological stress-induced activation of the sympathoadrenal stress axis prolongs the muscle pain observed after strenuous exercise. Methods: Adult male Sprague-Dawley rats were exposed to unpredictable sound stress and eccentric exercise. The involvement of the sympathoadrenal stress axis was evaluated by means of surgical interventions, systemic administration of epinephrine, and intrathecal β2-adrenergic receptor antisense. Results: Although sound stress alone did not modify nociceptive threshold, it prolonged eccentric exercise-induced mechanical hyperalgesia. Adrenal medullectomy (ADMdX) attenuated, and administration of stress levels of epinephrine to ADMdX rats mimicked this effect of sound stress. Knockdown of β2-adrenergic receptors by intrathecal antisense also attenuated sound stress-induced prolongation of eccentric exercise-induced hyperalgesia. Conclusion: Together, these results indicate that sympathoadrenal activation, by unpredictable sound stress, disrupts the capacity of nociceptors to sense recovery from eccentric exercise, leading to the prolongation of muscle hyperalgesia. This prolonged recovery from ergonomic pain is due, at least in part, to the activation of β2-adrenergic receptors on muscle nociceptors. Corresponding author. Address: University of California San Francisco, 513 Parnassus Ave, Room S709, San Francisco, CA 94143-0440. Tel.: +1 415 476 5108; fax: +1 415 476 6305. E-mail address: jon.levine@ucsf.edu (J.D. Levine). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Received May 30, 2019 Received in revised form July 16, 2019 Accepted August 01, 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Spinal cord stimulation prevents paclitaxel-induced mechanical and cold hypersensitivity and modulates spinal gene expression in rats Introduction: Paclitaxel-induced peripheral neuropathy (PIPN) is a common dose-limiting side effect of this cancer treatment drug. Spinal cord stimulation (SCS) has demonstrated efficacy for attenuating some neuropathic pain conditions. Objective: We aim to examine the inhibitory effect of SCS on the development of PIPN pain and changes of gene expression in the spinal cord in male rats after SCS. Methods: We examined whether traditional SCS (50 Hz, 6–8 h/session daily for 14 consecutive days) administered during paclitaxel treatment (1.5 mg/kg, i.p.) attenuates PIPN-related pain behavior. After SCS treatment, we performed RNA-seq of the lumbar spinal cord to examine which genes are differentially expressed after PIPN with and without SCS. Results: Compared to rats treated with paclitaxel alone (n = 7) or sham SCS (n = 6), SCS treatment (n = 11) significantly inhibited the development of paclitaxel-induced mechanical and cold hypersensitivity, without altering open-field exploratory behavior. RNA-seq showed that SCS induced upregulation of 836 genes and downregulation of 230 genes in the spinal cord of paclitaxel-treated rats (n = 3) as compared to sham SCS (n = 5). Spinal cord stimulation upregulated immune responses in paclitaxel-treated rats, including transcription of astrocyte- and microglial-related genes, but repressed transcription of multiple gene networks associated with synapse transmission, neuron projection development, γ-aminobutyric acid reuptake, and neuronal plasticity. Conclusion: Our findings suggest that traditional SCS may attenuate the development of pain-related behaviors in PIPN rats, possibly by causing aggregate inhibition of synaptic plasticity through upregulation and downregulation of gene networks in the spinal cord. Corresponding author. Address: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University, School of Medicine, Baltimore, MD 21205. Tel.: 410-502-5511; fax: 410-614-2109. E-mail address: yguan1@jhmi.edu (Y. Guan). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painrpts.com). Received April 25, 2019 Received in revised form August 06, 2019 Accepted August 10, 2019 This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Multidimensional screening for predicting pain problems in adults: a systematic review of screening tools and validation studies Screening tools allowing to predict poor pain outcomes are widely used. Often these screening tools contain psychosocial risk factors. This review (1) identifies multidimensional screening tools that include psychosocial risk factors for the development or maintenance of pain, pain-related distress, and pain-related disability across pain problems in adults, (2) evaluates the quality of the validation studies using Prediction model Risk Of Bias ASsessment Tool (PROBAST), and (3) synthesizes methodological concerns. We identified 32 articles, across 42 study samples, validating 7 screening tools. All tools were developed in the context of musculoskeletal pain, most often back pain, and aimed to predict the maintenance of pain or pain-related disability, not pain-related distress. Although more recent studies design, conduct, analyze, and report according to best practices in prognosis research, risk of bias was most often moderate. Common methodological concerns were identified, related to participant selection (eg, mixed populations), predictors (eg, predictors were administered differently to predictors in the development study), outcomes (eg, overlap between predictors and outcomes), sample size and participant flow (eg, unknown or inappropriate handling of missing data), and analysis (eg, wide variety of performance measures). Recommendations for future research are provided. Corresponding author. Address: Department of Experimental Clinical and Health Psychology, Faculty of Psychology and Educational Sciences, Ghent University, Henri Dunantlaan 2, B-9000 Gent, Belgium. Tel.: +32 92646392; fax: +32 9 264 64 89. E-mail address: Elke.Veirman@UGent.be (E. Veirman). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Received March 11, 2019 Received in revised form June 11, 2019 Accepted June 26, 2019 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Differences in itch and pain behaviors accompanying the irritant and allergic contact dermatitis produced by a contact allergen in mice Introduction: Irritant contact dermatitis (ICD) and allergic contact dermatitis (ACD) are inflammatory skin diseases accompanied by itch and pain. Irritant contact dermatitis is caused by chemical irritants eliciting an innate immune response, whereas ACD is induced by haptens additionally activating an adaptive immune response: After initial exposure (sensitization) to the hapten, a subsequent challenge can lead to a delayed-type hypersensitivity reaction. But, the sensory and inflammatory effects of sensitization (ICD) vs challenge of ACD are insufficiently studied. Therefore, we compared itch- and pain-like behaviors and inflammatory reactions evoked in mice during the sensitization (ICD) vs challenge phase (ACD) of application of the hapten, squaric acid dibutylester (SADBE). Objectives: Our aim was to compare itch- and pain-like behaviors and inflammatory reactions evoked in mice during the sensitization (ICD) vs challenge phase (ACD) of application of the hapten, squaric acid dibutylester (SADBE). Methods: Mice were sensitized on the abdomen with 1% SADBE (ACD) or vehicle treated (ICD, control). Spontaneous and stimulus-evoked itch- and pain-like behaviors were recorded in mice before and after 3 daily challenges of the cheek with 1% SADBE (ACD, ICD). Cutaneous inflammation was evaluated with clinical scoring, ultrasound imaging, skin thickness, histology, and analyses of selected biomarkers for contact dermatitis, IL-1β, TNF-α, CXCL10, and CXCR3. Results: Allergic contact dermatitis vs ICD mice exhibited more spontaneous site-directed scratching (itch) and wiping (pain). Allergic contact dermatitis—but not ICD—mice exhibited allodynia and hyperalgesia to mechanical and heat stimuli. Inflammatory mediators IL-1β and TNF-α were upregulated in both groups as well as the chemokine receptor, CXCR3. CXCL10, a CXCR3 ligand, was upregulated only for ACD. Inflammatory responses were more pronounced in ACD than ICD. Conclusion: These findings provide new information for differentiating the behavioral and inflammatory reactions to hapten-induced ICD and ACD. Corresponding author. Address: Department of Anesthesiology, Yale University School of Medicine, 333 Cedar St, New Haven, CT 06520. Tel.: 1-203-7372720; fax: 1-203-7371528. E-mail address: robert.lamotte@yale.edu (R.H. LaMotte). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Z. Zhang and N.M. Malewicz contributed equally. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painrpts.com). Received April 03, 2019 Received in revised form July 19, 2019 Accepted July 22, 2019 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Does the IASP definition of pain need updating? The current IASP definition of pain has come under renewed criticisms recently. There is a new momentum for its revision as reflected by the fact that IASP has now a Presidential Task Force dedicated to look into whether there is enough warrant to update the definition. I critically review all the major criticisms of the current definition in detail, and raise new difficulties rarely discussed before. I show that none of the major criticisms has enough warrant to force us to substantially revise the current definition. Combined with the discussion of the new difficulties, there is nonetheless a need to restate the definition using slightly different terminology that will make the original intent of the current definition clearer and more precise. A restatement of the definition is proposed and its potential is discussed in light of some empirical questions that remain. Corresponding author. Address: Department of Philosophy, University of British Columbia, Vancouver, BC, V6T 1Z1, Canada. Tel.:+1 604 822‐3292. E-mail address: maydede@mail.ubc.ca (M. Aydede). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Received April 01, 2019 Received in revised form May 13, 2019 Accepted June 29, 2019 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Insights on cannabidiol's antiallodynic and anxiolytic mechanisms of action in a model of neuropathic pain Recent studies have shown that cannabidiol (CBD) could have a great therapeutic potential for treating disorders such as chronic pain and anxiety. In the target article, the authors propose that CBD modulates serotonergic transmission and reverses allodynia and anxiety-like behaviour in a rat model of neuropathic pain. Furthermore, this study shows an antinociceptive effect mediated by TRPV1 and partially by 5-HT1A receptors, as well as an anxiolytic effect mediated by 5-HT1A receptors. Commentary on: De Gregorio D, McLaughlin RJ, Posa L, Ochoa-Sanchez R, Enns J, Lopez-Canul M, Aboud M, Maione S, Comai S, and Gobbi G. Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain. PAIN 2019;160:36–150. Address: EURIDOL Graduate School of Pain, University of Strasbourg, 8 allée du Général Rouvillois, 67000 Strasbourg, France. E-mail address: marion.schott3@etu.unistra.fr (M. Schott). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Received April 03, 2019 Received in revised form May 06, 2019 Accepted May 16, 2019 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Diurnal variation of inflammatory plasma proteins involved in pain Introduction: Proteomics is a powerful approach for biochemical research because it directly studies the main functional components of biochemical systems. The understanding of the normal fluctuations of the proteome in health is essential to identify pain-specific biomarkers. Objective: To investigate fluctuations of the plasma proteome in healthy pain-free individuals. Methods: Blood samples were structurally collected in the early morning and evening from 10 clinically healthy individuals (26.3 ± 3.3 years). High abundant proteins were removed from plasma, and proteins were then analysed by nanoliquid chromatography combined with mass spectrometry. In addition, an assay of 71 cytokines/chemokines/growth factors was analysed. Results: Multivariate statistical analysis displayed that there were up to 64 proteins whose expression levels were significantly altered between the plasma samples collected during the morning and evening; no changes existed for the assay. The levels of 34 proteins were increased and 30 proteins were decreased during the evening compared with the morning sample. The increased proteins were involved in the biological processes such as protein activation cascade, complement activation, and stress response. The decreased proteins were involved in regulation of endopeptidase activity, inflammatory response, and protein metabolic processes. Conclusion: The circadian variations in the plasma proteome stress the need to collect blood samples of both patients and controls at a fixed time of the day. The results in this study might be useful for better understanding of the complexity of individual variation in the human plasma proteome over time and provide a baseline for improved pain biomarker discovery. Corresponding author. Address: Division of Oral Diagnostics and Rehabilitation, Department of Dental Medicine, Karolinska Institutet, BOX 4064, SE141 04 Huddinge, Sweden. Tel.: 468 524 880 42. E-mail address: hajer.jasim@ki.se (H. Jasim). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.painrpts.com). Received April 30, 2019 Received in revised form June 27, 2019 Accepted June 29, 2019 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.

Sedentary behaviour facilitates conditioned pain modulation in middle-aged and older adults with persistent musculoskeletal pain: a cross-sectional investigation Introduction: Higher physical activity (PA) and lower sedentary behaviour (SB) levels have demonstrated beneficial effects on temporal summation (TS) and conditioned pain modulation (CPM) in healthy adults. This cross-sectional study investigated the relationships between PA and SB and TS/CPM responses in individuals with chronic musculoskeletal pain. Methods: Sixty-seven middle-aged and older adults with chronic musculoskeletal pain were recruited from the community. Questionnaires measuring demographics, pain, and psychological measures were completed. Physical activity/SB levels were measured using the International Physical Activity Questionnaire—short form and Sedentary Behaviour Questionnaire, respectively. Semmes monofilament was used to assess mechanical TS (MTS) at the most symptomatic (MTS-S) and a reference region (MTS-R); change in the pain scores (baseline-10th application) was used for analysis. Conditioned pain modulation procedure involved suprathreshold pressure pain threshold (PPT-pain4) administered before and after (CPM30sec, CPM60sec, and CPM90sec) conditioning stimulus (2 minutes; ∼12°C cold bath immersion). For analysis, PPT-pain4 (%) change scores were used. Results: PPT-pain4 (%) change scores at CPM30sec and CPM60sec demonstrated significant weak positive correlations with SB levels and weak negative correlations with PA measures. After adjusting for confounding variables, a significant positive association was found between SB (h/d) and PPT-pain4 (%) change scores at CPM30sec and CPM60sec. No significant associations between MTS and PA/SB measures. Conclusion: Sedentariness is associated with higher pain inhibitory capacity in people with chronic musculoskeletal pain. The observed relationship may be characteristic of a protective (sedentary) behaviour to enhance pain modulatory mechanism. Prospective longitudinal studies using objective PA/SB measures are required to validate the observed relationship in a larger sample size. Corresponding author. Address: School of Physiotherapy, University of Otago, PO Box 56, Dunedin 9054, New Zealand. Tel.: 64-3-479-3485. E-mail address: ramakrishnan.mani@otago.ac.nz (R. Mani). Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Received October 02, 2018 Received in revised form June 12, 2019 Accepted June 15, 2019 This is an open access article distributed under the Creative Commons Attribution-NoDerivatives License 4.0 (CC BY-ND) which allows for redistribution, commercial and non-commercial, as long as it is passed along unchanged and in whole, with credit to the author. © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.