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Interferons (IFNs) are cytokines that possess antiviral, antiproliferative, and immunomodulatory actions. IFN-α and IFN-β are two major family members of type-I IFNs and are used to treat diseases, including hepatitis and multiple sclerosis. Emerging evidence suggests that type-I IFN receptors (IFNARs) are also expressed by microglia, astrocytes, and neurons in the central and peripheral nervous systems. Apart from canonical transcriptional regulations, IFN-α and IFN-β can rapidly suppress neuronal activity and synaptic transmission via non-genomic regulation, leading to potent analgesia. IFN-γ is the only member of the type-II IFN family and induces central sensitization and microglia activation in persistent pain. We discuss how type-I and type-II IFNs regulate pain and infection via neuro-immune modulations, with special focus on neuroinflammation and neuro-glial interactions. We also highlight distinct roles of type-I IFNs in the peripheral and central nervous system. Insights into IFN signaling in nociceptors and their distinct actions in physiological vs. pathological and acute vs. chronic conditions will improve our treatments of pain after surgeries, traumas, and infections., Competing Interests: R-RJ is a consultant of Boston Scientific and received a research grant from the company. This activity is not related to this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Tan, Ji, Yeh and Ji.)

Virtual reality is a computer-generated environment that immerses the user in an interactive artificial world. This ability to distract from reality has been utilised for the purposes of providing pain relief from noxious stimuli. As technology rapidly matures, there is potential for anaesthetists and pain physicians to incorporate virtual reality devices as non-pharmacological therapy in a multimodal pain management strategy. This systematic narrative review evaluates clinical studies that used virtual reality in adult patients for management of acute and chronic pain. A literature search found 690 citations, out of which 18 studies satisfied the inclusion criteria. Studies were assessed for quality using the Jadad and Nottingham-Ottawa Scales. Agreement on scores between independent assessors was 0.87 (95%CI 0.73-0.94). Studies investigated virtual reality use: intra-operatively; for labour analgesia; for wound dressing changes; and in multiple chronic pain conditions. Twelve studies showed reduced pain scores in acute or chronic pain with virtual reality therapy, five studies showed no superiority to control treatment arms and in one study, the virtual reality exposure group had a worsening of acute pain scores. Studies were heterogeneous in: methods; patient population; and type of virtual reality used. These limitations suggest the evidence-base in adult patients is currently immature and more rigorous studies are required to validate the use of virtual reality as a non-pharmacological adjunct in multimodal pain management., (© 2020 Association of Anaesthetists.)

Background: Identifying how pain transitions from acute to chronic is critical in designing effective prevention and management techniques for patients' well-being, physically, psychosocially, and financially. There is an increasingly pressing need for a quantitative and predictive method to evaluate how low back pain trajectories are classified and, subsequently, how we can more effectively intervene during these progression stages., Methods: In order to better understand pain mechanisms, we investigated, using computational modeling, how best to describe pain trajectories by developing a platform by which we studied the transition of acute chronic pain., Results: The present study uses a computational neuroscience-based method to conduct such trajectory research, motivated by the use of hypothalamic-pituitary-adrenal (HPA) axis activity-history over a time-period as a way to mimic pain trajectories. A numerical simulation study is presented as a "proof of concept" for this modeling approach., Conclusions: This model and its simulation results have highlighted the feasibility and the potential of developing such a broader model for patient evaluations.

Modulation of pain may result from engagement of opioid receptors in multiple brain regions. Whether sensory and affective qualities of pain are differentially affected by brain opioid receptor circuits remains unclear. We previously reported that opioid actions within the rostral anterior cingulate cortex (ACC) produce selective modulation of affective qualities of neuropathic pain in rodents, but whether such effects may occur in other areas of the ACC is not known. Here, morphine was microinjected into 3 regions of the ACC or into the rostral ventromedial medulla (RVM), and pain behaviors in naive, sham, or spinal nerve ligated (SNL) rats were evaluated. In naive animals, the tail-flick response was inhibited by RVM, but not ACC, morphine. Anterior cingulate cortex morphine did not affect tactile allodynia (the von Frey test) or mechanical (Randall-Selitto) or thermal (Hargreaves) hyperalgesia in spinal nerve ligated rats. In contrary, RVM morphine reduced tactile allodynia and produced both antihyperalgesic and analgesic effects against mechanical and thermal stimuli as well as conditioned place preference selectively in nerve-injured rats. Within the RVM, opioids inhibit nociceptive transmission reflected in both withdrawal thresholds and affective pain behaviors. Activation of mu opioid receptors within specific rostral ACC circuits, however, selectively modulates affective dimensions of ongoing pain without altering withdrawal behaviors. These data suggest that RVM and ACC opioid circuits differentially modulate sensory and affective qualities of pain, allowing for optimal behaviors that promote escape and survival. Targeting specific ACC opioid circuits may allow for treatment of chronic pain while preserving the physiological function of acute pain.

Acute pain evokes protective neural and behavioral responses. Chronic pain, however, disrupts normal nociceptive processing. The prefrontal cortex (PFC) is known to exert top-down regulation of sensory inputs; unfortunately, how individual PFC neurons respond to an acute pain signal is not well characterized. We found that neurons in the prelimbic region of the PFC increased firing rates of the neurons after noxious stimulations in free-moving rats. Chronic pain, however, suppressed both basal spontaneous and pain-evoked firing rates. Furthermore, we identified a linear correlation between basal and evoked firing rates of PFC neurons, whereby a decrease in basal firing leads to a nearly 2-fold reduction in pain-evoked response in chronic pain states. In contrast, enhancing basal PFC activity with low-frequency optogenetic stimulation scaled up prefrontal outputs to inhibit pain. These results demonstrate a cortical gain control system for nociceptive regulation and establish scaling up prefrontal outputs as an effective neuromodulation strategy to inhibit pain., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

A growing body of evidence suggests that peptides may possess analgesic effects without tolerance development. The synthetic tetrapeptide Tyr-d-Arg-Phe-Gly-NH 2 was modified with the inclusion of a (d-Arg) 8 vector to prevent the action of endopeptidase and to increase the duration of the analgesic action of the tetrapeptide when administered orally. The aim of this study was to estimate the analgesic efficacy of the tetrapeptide with (d-Arg) 8 (tridecapeptide, TDP) in experimental models of acute and chronic pain. The analgesic effects of TDP were estimated using a model of acute visceral pain in mice (writhing test) and a model of chronic neuropathic pain (chronic constriction injury (CCI) of the sciatic nerve) in rats. The intravenous administration of morphine (0.32-1mg/kg) and TDP (0.32-1.8mg/kg) produced significant dose-related antinociceptive effects in the writhing test. The potency of TDP after i.g. administration was lower than that after i.v. administration but comparable with that of i.g. morphine. In the CCI model, TDP (0.1, 1 and 10mg/kg, i.g.) induced marked analgesia with repeated administration without any signs of tolerance. The single administration of TDP after morphine treatment (7days) produced a significant analgesic effect in morphine-tolerant rats, indicating the absence of cross-tolerance between these two drugs. The combined administration of TDP and morphine resulted in the reduction of analgesic tolerance to morphine. The absence of cross-tolerance to morphine and the ability to prevent morphine tolerance allows this compound to be a prospective candidate for chronic pain therapy. In order to find the target receptors for TDP, a docking study was performed. It was found that the molecule can bind to the NMDA receptor using electrostatic, hydrogen bonding and hydrophobic interactions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The treatment of chronic pain remains a challenge for clinicians worldwide, independent of its pathogenesis. It motivates several studies attempting to discover strategies to treat the disease. The in silico analysis using molecular docking approach demonstrated that the phthalimide N-(4methyl-phenyl)-4-methylphthalimide (MPMPH-1) presented high affinity to adenylyl-cyclase enzyme (AC). It also prominently reduced the mechanical hypersensitivity of mice challenged by Forskolin, an AC activator. This effect lasted for up to 48h after Forskolin injection, presenting activity longer than MDL-12330A (AC inhibitor). MPMPH-1 was also effective in reducing the hypersensitivity induced by IL-1β, bradykinin, prostaglandin E 2 or epinephrine, chemical mediators that have, among others, AC as pivotal protein in their signalling cascade to induce mechanical-pain behaviour. The compound presented marked inhibition in inflammatory-pain models induced by carrageenan, lipopolysaccharide or complete Freund's adjuvant, including neutrophil migration inhibition. Furthermore, it also seems to act in both peripheral and pain central-control pathways, being also effective in reducing the persistent cancer-pain behaviour induced by melanoma cells in mice. MPMPH-1 could represent a promising pharmacological tool to treat acute and chronic painful diseases, with good bioavailability, local activity, and lack of locomotor-activity interference. Further studies are necessary to determine the exact mechanism of action but it seems to involve AC enzyme as possible target., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

The dorsolateral prefrontal cortex (DLPFC) is a functionally and structurally heterogeneous region and a key node of several brain networks, implicated in cognitive, affective, and sensory processing. As such, the DLPFC is commonly activated in experimental pain studies, and shows abnormally increased function in chronic pain populations. Furthermore, several studies have shown that some chronic pains are associated with decreased left DLPFC gray matter and that successful interventions can reverse this structural abnormality. In addition, studies have indicated that noninvasive stimulation of the left DLPFC effectively treats some chronic pains. In this article, we review the neuroimaging literature regarding the role of the DLPFC and its potential as a therapeutic target for chronic pain conditions, including studies showing the involvement of the DLPFC in encoding and modulating acute pain and studies demonstrating the reversal of DLPFC functional and structural abnormalities after successful interventions for chronic pain. We also review studies of noninvasive brain stimulation of the DLPFC showing acute pain modulation and some effectiveness as a treatment for certain chronic pain conditions. We further discuss the network architecture of the DLPFC, and postulate mechanisms by which DLPFC stimulation alleviates chronic pain. Future work testing these mechanisms will allow for more effective therapies., Perspective: The structure and function of the DLPFC is abnormal in some chronic pain conditions. Upon successful resolution of pain, these abnormalities are reversed. Understanding the underlying mechanisms and the role of this region can lead to the development of an effective therapeutic target for some chronic pain conditions., (Copyright © 2017 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Neuropathic pain is a debilitating clinical problem and difficult to treat. Nerve injury causes a long-lasting reduction in K(+) channel expression in the dorsal root ganglion (DRG), but little is known about the epigenetic mechanisms involved. We found that nerve injury increased dimethylation of Lys9 on histone H3 (H3K9me2) at Kcna4, Kcnd2, Kcnq2 and Kcnma1 promoters but did not affect levels of DNA methylation on these genes in DRGs. Nerve injury increased activity of euchromatic histone-lysine N-methyltransferase-2 (G9a), histone deacetylases and enhancer of zeste homolog-2 (EZH2), but only G9a inhibition consistently restored K(+) channel expression. Selective knockout of the gene encoding G9a in DRG neurons completely blocked K(+) channel silencing and chronic pain development after nerve injury. Remarkably, RNA sequencing analysis revealed that G9a inhibition not only reactivated 40 of 42 silenced genes associated with K(+) channels but also normalized 638 genes down- or upregulated by nerve injury. Thus G9a has a dominant function in transcriptional repression of K(+) channels and in acute-to-chronic pain transition after nerve injury.

Objective: To investigate the changes in paraspinal muscle cross-sectional area (CSA) and composition, using the digital data from lumbar spine MRIs of patients with acute and chronic low back pain (LBP)., Methods: In total, 178 patients with unilateral LBP who had lumbar MRI examination were recruited. The data were obtained by a retrospective documentation audit. The CSAs and mean signal intensities of the bilateral paraspinal muscles [psoas major (PM), quadratus lumborum, multifidus (MF) and erector spinae (ES)] were measured, and the percentage of fat infiltration was calculated. The data between the painful side and non-painful side were compared, and between-group comparisons were tested. 42 patients with chronic unilateral LBP could indicate the problem level, and the CSA and mean signal intensity of the MF muscle were analysed at the problem level, and one vertebral above and one vertebral level below the problem level., Results: The CSAs of the PM and ES muscles were significantly decreased in the acute LBP group, while in the chronic LBP group, significant reduction in CSA was found in the MF and ES muscles on the painful side compared with the non-painful side. The mean signal intensity and fat content of the ES muscle on the painful side in the chronic LBP group was significantly higher than that on the painful side in the acute LBP group. The significant decrease of CSA in the MF muscle was found at multiple levels on the painful side., Conclusion: The present findings show that there is selective ipsilateral atrophy of paraspinal muscles, specific to the symptomatic side, in patients with acute and chronic LBP. The reduction of the muscle CSA and increased fatty infiltration occurred synchronously, and the extent of change is significantly greater in chronic LBP in the ES muscle. Atrophy of the MF muscle appears to be at multiple levels but side specific in relation to symptoms in patients with chronic LBP, and the decreased muscle CSA may occur prior to fatty infiltration., Advances in Knowledge: There are specific paraspinal muscles undergoing atrophy and fatty infiltration in patients with acute and chronic LBP on the symptomatic side. The CSA of the MF muscle decreased at multiple levels on the symptomatic side in patients with chronic unilateral LBP, which may occur prior to fatty infiltration.

Background Context: Primary care clinicians need to identify candidates for early interventions to prevent patients with acute pain from developing chronic pain., Purpose: We conducted a 2-year prospective cohort study of risk factors for the progression to chronic pain and developed and internally validated a clinical decision rule (CDR) that stratifies patients into low-, medium-, and high-risk groups for chronic pain., Study Design/setting: This is a prospective cohort study in primary care., Patient Sample: Patients with acute low back pain (LBP, ≤30 days duration) were included., Outcome Measures: Outcome measures were self-reported perceived nonrecovery and chronic pain., Methods: Patients were surveyed at baseline, 6 months, and 2 years. We conducted bivariate and multivariate regression analyses of demographic, clinical, and psychosocial variables for chronic pain outcomes, developed a CDR, and assessed its performance by calculating the bootstrapped areas under the receiver-operating characteristic curve (AUC) and likelihood ratios., Results: Six hundred five patients enrolled: 13% had chronic pain at 6 months and 19% at 2 years. An eight-item CDR was most parsimonious for classifying patients into three risk levels. Bootstrapped AUC was 0.76 (0.70-0.82) for the 6-month CDR. Each 10-point score increase (60-point range) was associated with an odds ratio of 11.1 (10.8-11.4) for developing chronic pain. Using a less than 5% probability of chronic pain as the cutoff for low risk and a greater than 40% probability for high risk, likelihood ratios were 0.26 (0.14-0.48) and 4.4 (3.0-6.3) for these groups, respectively., Conclusions: A CDR was developed that may help primary care clinicians classify patients with strictly defined acute LBP into low-, moderate-, and high-risk groups for developing chronic pain and performed acceptably in 1,000 bootstrapped replications. Validation in a separate sample is needed., (Copyright © 2015 Elsevier Inc. All rights reserved.)

This review presents the current data in the literature about the importance of the cortex and subcortical structures of the brain in the perception of acute and chronic pain. Discussed the importance of various areas of the brain in perception discriminative and affective components of pain. Discusses also gender differences in pain perception depending on the functional activity of brain cortex and antinociceptive subcortical structures. Analyzed the morphological changes of cortical and subcortical structures of the brain in chronic pain syndromes. It is proved that the decrease in the volume of gray and white matter of cerebral cortex and subcortical structures is a consequence and not the cause of chronic pain syndrome. Discusses the features activate and deactivate certain areas of the cortex of the brain in acute and chronic pain. Analyzed same features the activation of several brain structures in migraine and cluster headache.

Thalamocortical oscillations are critical for sensory perception. Although pain is known to disrupt synchrony in thalamocortical oscillations, evidence in the literature is controversial. Thalamocortical coherence has been reported to be increased in patients with neurogenic pain but decreased in a rat model of central pain. Moreover, theta (4 to 8 Hz) oscillations in primary somatosensory (S1) cortex are speculated to predict pain in humans. To date, the link between pain and network oscillations in animal models has been understudied. Thus, we tested the hypothesis that pain disrupts thalamocortical coherence and S1 theta power in two rat models of pain. We recorded electrocorticography (ECoG) waveforms over S1 and local field potentials (LFP) within ventral posterolateral thalamus in freely behaving rats under spontaneous (stimulus-independent) pain conditions. Rats received intradermal capsaicin injection (Cap) in the hindpaw, followed hours later by chronic constriction injury (CCI) of the sciatic nerve lasting several days. Our results show that pain decreases coherence between LFP and ECoG waveforms in the 2- to 30-Hz range, and increases ECoG power in the theta range. These changes are short-lasting after Cap and longer-lasting after CCI. These data might be particularly relevant to preclinical correlates of spontaneous pain-like behavior, with potential implications to clinical biomarkers of ongoing pain., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

The persistence of pain after surgery increases the recovery interval from surgery to a normal quality of life. AYX1 is a DNA-decoy drug candidate designed to prevent post-surgical pain following a single intrathecal injection. Tissue injury causes a transient activation of the transcription factor EGR1 in the dorsal root ganglia-dorsal horn network, which then triggers changes in gene expression that induce neuronal hypersensitivity. AYX1 is a potent, specific inhibitor of EGR1 activity that mimics the genomic EGR1-binding sequence. Administered in the peri-operative period, AYX1 dose dependently prevents mechanical hypersensitivity in models of acute incisional (plantar), inflammatory (CFA), and chronic neuropathic pain (SNI) in rats. Furthermore, in a knee surgery model evaluating functional measures of postoperative pain, AYX1 improved weight-bearing incapacitance and spontaneous rearing compared to control. These data illustrate the potential clinical therapeutic benefits of AYX1 for preventing the transition of acute to chronic post-surgical pain., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

We have previously shown that activation of protein kinase Cε (PKCε) in male rats induces a chronic, long-lasting change in nociceptors such that a subsequent exposure to proinflammatory mediators produces markedly prolonged mechanical hyperalgesia. This neuroplastic change, hyperalgesic priming, is dependent on activation of cytoplasmic polyadenylation element-binding protein (CPEB), downstream of PKCε, and consequent translation of mRNAs in the peripheral terminal of the nociceptor. Since α calmodulin-dependent protein kinase II (αCaMKII), a molecule implicated in neuroplasticity, is a target of CPEB and can also affect CPEB function, we investigated its role in the transition from acute to chronic pain. Priming induced by direct activation of PKCε can be prevented by inhibition of αCaMKII. In addition, direct activation of αCaMKII induces priming, which was not prevented by pretreatment with PKCε antisense, suggesting that αCaMKII is downstream of PKCε in the induction of priming. Activation of ryanodine receptors (RyRs), which can lead to activation of αCaMKII, also induced priming, in a calcium- and αCaMKII-dependent manner. Similarly, inhibition of the RyR and a calcium buffer prevented induction of priming by PKCε. Unlike activation of PKCε, ryanodine and αCaMKII induced priming in female as well as male rats. Our results demonstrate a contribution of αCaMKII to induction of hyperalgesic priming, a phenomenon implicated in the transition from acute to chronic pain.

Background: Despite advances in our understanding of basic mechanisms driving post-surgical pain, treating incision-induced pain remains a major clinical challenge. Moreover, surgery has been implicated as a major cause of chronic pain conditions. Hence, more efficacious treatments are needed to inhibit incision-induced pain and prevent the transition to chronic pain following surgery. We reasoned that activators of AMP-activated protein kinase (AMPK) may represent a novel treatment avenue for the local treatment of incision-induced pain because AMPK activators inhibit ERK and mTOR signaling, two important pathways involved in the sensitization of peripheral nociceptors., Results: To test this hypothesis we used a potent and efficacious activator of AMPK, resveratrol. Our results demonstrate that resveratrol profoundly inhibits ERK and mTOR signaling in sensory neurons in a time- and concentration-dependent fashion and that these effects are mediated by AMPK activation and independent of sirtuin activity. Interleukin-6 (IL-6) is thought to play an important role in incision-induced pain and resveratrol potently inhibited IL-6-mediated signaling to ERK in sensory neurons and blocked IL-6-mediated allodynia in vivo through a local mechanism of action. Using a model of incision-induced allodynia in mice, we further demonstrate that local injection of resveratrol around the surgical wound strongly attenuates incision-induced allodynia. Intraplantar IL-6 injection and plantar incision induces persistent nociceptive sensitization to PGE2 injection into the affected paw after the resolution of allodynia to the initial stimulus. We further show that resveratrol treatment at the time of IL-6 injection or plantar incision completely blocks the development of persistent nociceptive sensitization consistent with the blockade of a transition to a chronic pain state by resveratrol treatment., Conclusions: These results highlight the importance of signaling to translation control in peripheral sensitization of nociceptors and provide further evidence for activation of AMPK as a novel treatment avenue for acute and chronic pain states.