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Papers Of The Week
2024 May 20 - Brain Behav Immun
Editor's Pick

IRF7 overexpression alleviates CFA-induced inflammatory pain by inhibiting nuclear factor-κB activation and pro-inflammatory cytokines expression in rats.

Authors: Jiang S, Li Z, Huang SJ, Zou W, Luo JG
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It is known that nerve signals arising from sites of inflammation lead to persistent changes in the spinal cord and contribute to the amplification and persistence of pain. Nevertheless, the underlying mechanisms have not yet been completely elucidated. We identified differentially expressed genes in the lumbar (L4-L6) segment of the spinal cord from complete Freund’s adjuvant (CFA) rats compared to control animals via high throughput sequencing. Based on differential gene expression analysis, we selected interferon regulatory factor 7 (IRF7) for follow-up experiments to explore its antinociceptive potential.

2024 May 15 - Cell
Editor's Pick

Innervation of nociceptor neurons in the spleen promotes germinal center responses and humoral immunity.

Authors: Wu M, Song G, Li J, Song Z, Zhao B, Liang L, Li W, Hu H, Tu H, Li S, Li P, Zhang B, Wang W, Zhang Y, Zhang W, Zheng W, Wang J, Wen Y, Wang K, Li A, Zhou T, Zhang Y, Li H
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Peripheral sensory neurons widely innervate various tissues to continuously monitor and respond to environmental stimuli. Whether peripheral sensory neurons innervate the spleen and modulate splenic immune response remains poorly defined. Here, we demonstrate that nociceptive sensory nerve fibers extensively innervate the spleen along blood vessels and reach B cell zones. The spleen-innervating nociceptors predominantly originate from left T8-T13 dorsal root ganglia (DRGs), promoting the splenic germinal center (GC) response and humoral immunity. Nociceptors can be activated by antigen-induced accumulation of splenic prostaglandin E (PGE) and then release calcitonin gene-related peptide (CGRP), which further promotes the splenic GC response at the early stage. Mechanistically, CGRP directly acts on B cells through its receptor CALCRL-RAMP1 via the cyclic AMP (cAMP) signaling pathway. Activating nociceptors by ingesting capsaicin enhances the splenic GC response and anti-influenza immunity. Collectively, our study establishes a specific DRG-spleen sensory neural connection that promotes humoral immunity, suggesting a promising approach for improving host defense by targeting the nociceptive nervous system.

2024 May 16 - Nat Rev Neurol
Editor's Pick

Deciphering nociplastic pain: clinical features, risk factors and potential mechanisms.

Authors: Kaplan CM, Kelleher E, Irani A, Schrepf A, Clauw DJ, Harte SE
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Nociplastic pain is a mechanistic term used to describe pain that arises or is sustained by altered nociception, despite the absence of tissue damage. Although nociplastic pain has distinct pathophysiology from nociceptive and neuropathic pain, these pain mechanisms often coincide within individuals, which contributes to the intractability of chronic pain. Key symptoms of nociplastic pain include pain in multiple body regions, fatigue, sleep disturbances, cognitive dysfunction, depression and anxiety. Individuals with nociplastic pain are often diffusely tender – indicative of hyperalgesia and/or allodynia – and are often more sensitive than others to non-painful sensory stimuli such as lights, odours and noises. This Review summarizes the risk factors, clinical presentation and treatment of nociplastic pain, and describes how alterations in brain function and structure, immune processing and peripheral factors might contribute to the nociplastic pain phenotype. This article concludes with a discussion of two proposed subtypes of nociplastic pain that reflect distinct neurobiological features and treatment responsivity.

2024 May 10 - Brain Behav Immun
Editor's Pick

Bone morphogenetic protein 4 derived from the cerebrospinal fluid in patients with postherpetic neuralgia induces allodynia via the crosstalk between microglia and astrocyte.

Authors: Chen K, Wei X, Zhang W, Wang R, Wang Y, Yang L
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During postherpetic neuralgia (PHN), the cerebral spinal fluid (CSF) possesses the capability to trigger glial activation and inflammation, yet the specific changes in its composition remain unclear. Recent findings from our research indicate elevations of central bone morphogenetic protein 4 (BMP4) during neuropathic pain (NP), serving as an independent modulator of glial cells. Herein, the aim of the present study is to test the CSF-BMP4 expressions and its role in the glial modulation in the process of PHN.

2024 May 03 - Pain
Editor's Pick

Methods for pragmatic randomized clinical trials of pain therapies: IMMPACT statement.

Authors: Hohenschurz-Schmidt D, Cherkin D, Rice ASC, Dworkin RH, Turk DC, McDermott MP, Bair MJ, DeBar LL, Edwards RR, Evans SR, Farrar JT, Kerns RD, Rowbotham MC, Wasan AD, Cowan P, Ferguson M, Freeman R, Gewandter JS, Gilron I, Grol-Prokopczyk H, Iyengar S, Kamp C, Karp BI, Kleykamp BA, Loeser JD, Mackey S, Malamut R, McNicol E, Patel KV, Schmader K, Simon L, Steiner DJ, Veasley C, Vollert J
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Pragmatic, randomized, controlled trials hold the potential to directly inform clinical decision making and health policy regarding the treatment of people experiencing pain. Pragmatic trials are designed to replicate or are embedded within routine clinical care and are increasingly valued to bridge the gap between trial research and clinical practice, especially in multidimensional conditions, such as pain and in nonpharmacological intervention research. To maximize the potential of pragmatic trials in pain research, the careful consideration of each methodological decision is required. Trials aligned with routine practice pose several challenges, such as determining and enrolling appropriate study participants, deciding on the appropriate level of flexibility in treatment delivery, integrating information on concomitant treatments and adherence, and choosing comparator conditions and outcome measures. Ensuring data quality in real-world clinical settings is another challenging goal. Furthermore, current trials in the field would benefit from analysis methods that allow for a differentiated understanding of effects across patient subgroups and improved reporting of methods and context, which is required to assess the generalizability of findings. At the same time, a range of novel methodological approaches provide opportunities for enhanced efficiency and relevance of pragmatic trials to stakeholders and clinical decision making. In this study, best-practice considerations for these and other concerns in pragmatic trials of pain treatments are offered and a number of promising solutions discussed. The basis of these recommendations was an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks.

2024 May 09 - J Clin Invest
Editor's Pick

Peripherally targeted analgesia via AAV-mediated sensory neuron-specific inhibition of multiple pronociceptive sodium channels.

Authors: Shin SM, Itson-Zoske B, Fan F, Xiao Y, Qiu C, Cummins TR, Hogan QH, Yu H
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This study reports that targeting intrinsically disordered regions of NaV1.7 protein facilitates discovery of sodium channel inhibitory peptide aptamers (NaViPA) for adeno-associated virus (AAV)-mediated, sensory neuron-specific analgesia. A multipronged inhibition of INa1.7, INa1.6, INa1.3, and INa1.1. but not INa1.5 and INa1.8 was found for a prototype, named NaViPA1, which was derived from the NaV1.7 intracellular loop 1 and is conserved among the TTXs NaV subtypes. NaViPA1 expression in primary sensory neurons (PSNs) of dorsal root ganglia (DRG) produced significant inhibition of TTXs INa but not TTXr INa. DRG injection of AAV6-encoded NaViPA1 significantly attenuated evoked and spontaneous pain behaviors in both male and female rats with neuropathic pain induced by tibial nerve injury (TNI). Whole-cell current clamp of the PSNs showed that NaViPA1 expression normalized PSN excitability in TNI rats, suggesting that NaViPA1 attenuated pain by reversal of injury-induced neuronal hypersensitivity. Immunohistochemistry revealed efficient NaViPA1 expression restricted in PSNs and their central and peripheral terminals, indicating PSN-restricted AAV biodistribution. Inhibition of sodium channels by NaViPA1 was replicated in the human iPSC-derived sensory neurons. These results summate that NaViPA1 is a promising analgesic lead that, combined with AAV-mediated PSN-specific block of multiple TTXs NaVs, has potential as peripheral nerve-restricted analgesic therapeutics.

2024 May 08 - Sci Transl Med
Editor's Pick

MRGPRX4 mediates phospho-drug-associated pruritus in a humanized mouse model.

Authors: Chien DC, Limjunyawong N, Cao C, Meixiong J, Peng Q, Ho CY, Fay JF, Roth BL, Dong X
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The phosphate modification of drugs is a common chemical strategy to increase solubility and allow for parenteral administration. Unfortunately, phosphate modifications often elicit treatment- or dose-limiting pruritus through an unknown mechanism. Using unbiased high-throughput drug screens, we identified the Mas-related G protein-coupled receptor X4 (MRGPRX4), a primate-specific, sensory neuron receptor previously implicated in itch, as a potential target for phosphate-modified compounds. Using both G-mediated calcium mobilization and G protein-independent GPCR assays, we found that phosphate-modified compounds potently activate MRGPRX4. Furthermore, a humanized mouse model expressing MRGPRX4 in sensory neurons exhibited robust phosphomonoester prodrug-evoked itch. To characterize and confirm this interaction, we further determined the structure of MRGPRX4 in complex with a phosphate-modified drug through single-particle cryo-electron microscopy (cryo-EM) and identified critical amino acid residues responsible for the binding of the phosphate group. Together, these findings explain how phosphorylated drugs can elicit treatment-limiting itch and identify MRGPRX4 as a potential therapeutic target to suppress itch and to guide future drug design.

2024 May 04 - Brain Behav Immun
Editor's Pick

Gut microbiota promotes pain chronicity in Myosin1A deficient male mice.

Authors: Reynders A, Anissa Jhumka Z, Gaillard S, Mantilleri A, Malapert P, Magalon K, Etzerodt A, Salio C, Ugolini S, Castets F, Saurin AJ, Serino M, Hoeffel G, Moqrich A
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Chronic pain is a heavily debilitating condition and a huge socio-economic burden, with no efficient treatment. Over the past decade, the gut microbiota has emerged as an important regulator of nervous system’s health and disease states. Yet, its contribution to the pathogenesis of chronic somatic pain remains poorly documented. Here, we report that male but not female mice lacking Myosin1a (KO) raised under single genotype housing conditions (KO-SGH) are predisposed to develop chronic pain in response to a peripheral tissue injury. We further underscore the potential of MYO1A loss-of-function to alter the composition of the gut microbiota and uncover a functional connection between the vulnerability to chronic pain and the dysbiotic gut microbiota of KO-SGH males. As such, parental antibiotic treatment modifies gut microbiota composition and completely rescues the injury-induced pain chronicity in male KO-SGH offspring. Furthermore, in KO-SGH males, this dysbiosis is accompanied by a transcriptomic activation signature in the dorsal root ganglia (DRG) macrophage compartment, in response to tissue injury. We identify CD206CD163 and CD206CD163 as the main subsets of DRG resident macrophages and show that both are long-lived and self-maintained and exhibit the capacity to monitor the vasculature. Consistently, in vivo depletion of DRG macrophages rescues KO-SGH males from injury-induced chronic pain underscoring a deleterious role for DRG macrophages in a Myo1a-loss-of function context. Together, our findings reveal gene-sex-microbiota interactions in determining the predisposition to injury-induced chronic pain and point-out DRG macrophages as potential effector cells.

2024 May 02 - Pain
Editor's Pick

The downside to choice: instrumental control increases conditioned nocebo hyperalgesia.

Authors: Tang B, Livesey E, Colagiuri B
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Nocebo hyperalgesia is a pervasive problem in which the treatment context triggers negative expectations that exacerbate pain. Thus, developing ethical strategies to mitigate nocebo hyperalgesia is crucial. Emerging research suggests that choice has the capacity to reduce nocebo side effects, but choice effects on nocebo hyperalgesia have not been explored. This study investigated the impact of choice on conditioned nocebo hyperalgesia using a well-established electrocutaneous pain paradigm where increases in noxious stimulation were surreptitiously paired with the activation of a sham device. In study 1, healthy volunteers (N = 104) were randomised to choice over (nocebo) treatment administration, nocebo administration without choice, or a natural history control group. Nocebo hyperalgesia was greater for those with choice than no choice, suggesting that choice increased rather than diminished nocebo hyperalgesia. Study 2 tested whether providing positive information about the benefits of choice in coping with pain could counteract heightened nocebo hyperalgesia caused by choice. A different sample of healthy adults (N = 137) were randomised to receive nocebo treatment with choice and positive choice information, choice only, or no choice. The positive choice information failed to attenuate the effect of choice on nocebo hyperalgesia. The current results suggest that, rather than decreasing nocebo hyperalgesia, treatment choice may exacerbate pain outcomes when a painful procedure is repeatedly administered. As such, using choice as a strategy to mitigate nocebo outcomes should be treated with caution.

2024 May 03 - Brain
Editor's Pick

How side effects can improve treatment efficacy: a randomized trial.

Authors: Schenk LA, Fadai T, Büchel C
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While treatment side effects may adversely impact patients, they could also potentially function as indicators for effective treatment. In this study, we investigated whether and how side effects can trigger positive treatment expectations and enhance treatment outcomes. In this preregistered trial (DRKS00026648), 77 healthy participants were made to believe that they will receive fentanyl nasal sprays before receiving thermal pain in a controlled experimental setting. However, nasal sprays did not contain fentanyl, rather they either contained capsaicin to induce a side effect (mild burning sensation) or saline (inert). After the first session, participants were randomized to two groups and underwent functional magnetic resonance imaging (fMRI). One group continued to believe that the nasal sprays could contain fentanyl while the other group was explicitly informed that no fentanyl was included. This allowed for the independent manipulation of the side effects and the expectation of pain relief. Our results revealed that nasal sprays with a side effect lead to lower pain than inert nasal sprays without side effects. The influence of side effects on pain was dependent on individual beliefs about how side effects are related to treatment outcome, as well as on expectations about received treatment. FMRI data indicated an involvement of the descending pain modulatory system including the anterior cingulate cortex and the periaqueductal gray during pain after experiencing a nasal spray with side effects. In summary, our data show that mild side effects can serve as a signal for effective treatment thereby influencing treatment expectations and outcomes, which is mediated by the descending pain modulatory system. Using these mechanisms in clinical practice could provide an efficient way to optimize treatment outcome. In addition, our results indicate an important confound in clinical trials, where a treatment (with potential side effects) is compared to placebo.

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