The current IASP definition of pain as "An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage" was recommended by the Subcommittee on Taxonomy and adopted by the IASP Council in 1979. This definition has become accepted widely by health care professionals and researchers in the pain field and adopted by several professional, governmental, and nongovernmental organizations, including the World Health Organization. In recent years, some in the field have reasoned that advances in our understanding of pain warrant a re-evaluation of the definition and have proposed modifications. Therefore, in 2018, the IASP formed a 14-member, multinational Presidential Task Force comprising individuals with broad expertise in clinical and basic science related to pain to evaluate the current definition and accompanying note and recommend whether they should be retained or changed. This review provides a synopsis of the critical concepts, the analysis of comments from the IASP membership and public, and the committee's final recommendations for revisions to the definition and notes, which were discussed over a 2-year period. The task force ultimately recommended that the definition of pain be revised to "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage," and that the accompanying notes be updated to a bulleted list that included the etymology. The revised definition and notes were unanimously accepted by the IASP Council early this year."Scientific and medical definitions are tools. Even when we recognize them as imperfect or provisional, awaiting replacement by an improved version, they perform work that cannot be accomplished by less precise instruments." David B. Morris [27] * Letter to the task force from M. Aydede titled "On the IASP Presidential Task Force's proposal for a new definition of 'pain'," dated

With the ubiquitous deployment of wireless systems and pervasive availability of smart devices, indoor localization is empowering numerous location-based services. With the established radio maps, WiFi fingerprinting has become one of the most practical approaches to localize mobile users. However, most fingerprint-based localization algorithms are computation-intensive, with heavy dependence on both offline training phase and online localization phase. In this paper, we propose CNNLoc, a Convolutional Neural Network (CNN) based indoor localization system with WiFi fingerprints for multi-building and multi-floor localization. Specifically, we devise a novel classification model and a novel positioning model by combining a Stacked Auto-Encoder (SAE) with a one-dimensional CNN. The SAE is utilized to precisely extract key features from sparse Received Signal Strength (RSS) data while the CNN is trained to effectively achieve high accuracy in the positioning phase. We evaluate the proposed system on the UJIIndoorLoc dataset and Tampere dataset and compare the performance with several state-of-the-art methods. Moreover, we further propose a newly collected WiFi fingerprinting dataset UTSIndoorLoc and test the positioning model of CNNLoc on it. The results show CNNLoc outperforms the existing solutions with 100% and 95% success rates on building-level localization and floor-level localization, respectively.

Numerous studies have implicated the cAMP-protein kinase A (PKA) pathway in producing hyperexcitability of dorsal root ganglia (DRG) sensory neurons under conditions associated with pain. Evidence is presented for roles of both the cAMP-PKA and cGMP-protein kinase G (PKG) pathways in maintaining neuronal hyperexcitability and behavioral hyperalgesia in a neuropathic pain model: chronic compression of the DRG (CCD treatment). Lumbar DRGs were compressed by a steel rod inserted into the intervertebral foramen. Thermal hyperalgesia was revealed by shortened latencies of foot withdrawal to radiant heat. Intracellular recordings were obtained in vitro from lumbar ganglia after in vivo DRG compression. Activators of the cAMP-PKA pathway, 8-Br-cAMP and Sp-cAMPS, and of the cGMP-PKG pathway, 8-Br-cGMP and Sp-cGMPS, increased the hyperexcitability of DRG neurons already produced by CCD treatment, as shown by further decreases in action potential threshold and increased repetitive discharge during depolarization. The adenylate cyclase inhibitor, SQ22536, the PKA antagonist, Rp-cAMPS, the guanylate cyclase inhibitor, ODQ, and the PKG inhibitor, Rp-8-pCPT-cGMPS, reduced the hyperexcitability of CCD DRG neurons. In vivo application of PKA and PKG antagonists transiently depressed behavioral hyperalgesia induced by CCD treatment. Unexpectedly, application of these agonists and antagonists to ganglia of naïve, uninjured animals had little effect on electrophysiological properties of DRG neurons and no effect on foot withdrawal, suggesting that sensitizing actions of these pathways in the DRG are enabled by prior injury or stress. The only effect observed in uncompressed ganglia was modest depolarization of DRG neurons by PKA and PKG agonists. CCD treatment also depolarized DRG neurons, but CCD-induced depolarization was not affected by agonists or antagonists of these pathways.

Zheng J-H, Walters ET, Song X-J. Dissociation of dorsal root ganglion neurons induces hyperexcitability that is maintained by increased responsiveness to cAMP and cGMP. J Neurophysiol 97: [15][16][17][18][19][20][21][22][23][24][25] 2007. First published October 18, 2006; doi:10.1152/jn.00559.2006. Injury or inflammation affecting sensory neurons in dorsal root ganglia (DRG) causes hyperexcitability of DRG neurons that can lead to spontaneous firing and neuropathic pain. Recent results indicate that after chronic compression of DRG (CCD treatment), both hyperexcitability of neurons in intact DRG and behaviorally expressed hyperalgesia are maintained by concurrent activity in cAMP-protein kinase A (PKA) and cGMPprotein kinase G (PKG) signaling pathways. We report here that when tested under identical conditions, dissociation produces a pattern of hyperexcitability in small DRG neurons similar to that produced by CCD treatment, manifest as decreased action potential (AP) current threshold, increased AP duration, increased repetitive firing to depolarizing pulses, increased spontaneous firing and resting depolarization. A novel feature of this hyperexcitability is its early expression-as soon as testing can be conducted after dissociation (ϳ2 h). Both forms of injury increase the electrophysiological responsiveness of the neurons to activation of cAMP-PKA and cGMP-PKG pathways as indicated by enhancement of hyperexcitability by agonists of these pathways in dissociated or CCD-treated neurons but not in control neurons. Although inflammatory signals are known to activate cAMP-PKA pathways, dissociation-induced hyperexcitability is unlikely to be triggered by signals released from inflammatory cells recruited to the DRG because of insufficient time for recruitment during the dissociation procedure. Inhibition by specific antagonists indicates that continuing activation of cAMP-PKA and cGMP-PKG pathways is required to maintain hyperexcitability after dissociation. The reduction of hyperexcitability by blockers of adenylyl cyclase and soluble guanylyl cyclase after dissociation suggests a continuing release of autocrine and/or paracrine factors from dissociated neurons and/or satellite cells, which activate both cyclases and help to maintain acute, injury-induced hyperexcitability of DRG neurons. I N T R O D U C T I O NDamage to the peripheral nervous system produces longlasting hyperexcitability of sensory neurons in diverse species (Walters 1994). In mammals, injury affecting the axons or somata of sensory neurons having their somata in dorsal root ganglia (DRGs) often causes hyperexcitability that may lead to spontaneous firing, neuropathic pain, and paresthesias (Devor 1994;Zimmermann 2001). Although electrophysiological mechanisms contributing to the expression of hyperexcitability in DRG neuronal somata after injury to the peripheral nervous system have been investigated intensively, less is known about the signals that induce and maintain this hyperexcitability (Ji and Strichartz 2004). Recently we showed that t...

Treating bone cancer pain continues to be a clinical challenge and underlying mechanisms of bone cancer pain remain elusive. Here, we report that EphB1 receptor forward signaling in the spinal cord is critical to the development of bone cancer pain and morphine tolerance in treating bone cancer pain. Tibia bone cavity tumor cell implantation (TCI) produces bone cancer-related thermal hyperalgesia, mechanical allodynia, spontaneous and movement-evoked pain behaviors, and bone destruction. Production and persistence of these pain behaviors are well correlated with TCI-induced upregulation of EphB1 receptor and its ligand ephrinB2 in the dorsal horn and primary sensory neurons. Spinal administration of an EphB1 receptor blocking reagent EphB2-Fc prevents and reverses bone cancer pain behaviors and the associated induction of c-Fos and activation of astrocytes and microglial cells, NR1 and NR2B receptors, Src within the N-methyl-D-aspartate receptor complex, and the subsequent Ca 2þ -dependent signals. The exogenous ligand ephrinB2-Fc upregulates level of phosphorylation of NR1 and NR2B receptors depending on the activation of EphB1 receptor. Spinal administration of EphB2-Fc and ephrinB2-Fc induces downregulation of EphB1 and ephrinB2, respectively, accompanied with increased activity of matrix metalloproteinase (MMP)-2/9. Blocking MMP-2 or MMP-9 reverses EphB1-Fc treatment-induced downregulation of EphB1 receptor. In addition, spinal blocking or targeted mutation of EphB1 receptor reverses morphine tolerance in treating bone cancer pain in rats and defensive pain in mice. These findings show a critical mechanism underlying the pathogenesis of bone cancer pain and suggest a potential target for treating bone cancer pain and improving analgesic effect of morphine clinically. Cancer Res; 71(13); 4392-402. Ó2011 AACR.

Resveratrol directly suppresses morphine-induced microglial activation through activating AMPK, resulting in significant attenuation of morphine antinociceptive tolerance.

EphB receptor tyrosine kinases, which play important roles in synaptic connection and plasticity during development and in matured nervous system, have recently been implicated in processing of pain after nerve injury and morphine dependence. Subtypes of the EphB receptors that may contribute to the neuropathic pain and morphine dependence have not been identified. Here we demonstrate that the subtype EphB1 receptor is necessary for development of neuropathic pain and physical dependence on morphine. The results showed that peripheral nerve injury produced thermal hyperalgesia in wild-type (EphB1+/+) control littermate mice, but not in EphB1 receptor homozygous knockout (EphB1-/-) and heterozygous knockdown (EphB1+/-) mice. Hyperalgesia in the wild-type mice was inhibited by intrathecal administration of an EphB receptor blocking reagent EphB2-Fc (2 μg). Intrathecal administration of an EphB receptor activator ephrinB1-Fc (1 μg) evoked thermal hyperalgesia in EphB1+/+, but not EphB1-/-and EphB1+/-mice. Cellularly, nerve injury-induced hyperexcitability of the medium-sized dorsal root ganglion neurons was prevented in EphB1-/-and EphB1+/-mice. In chronically morphine-treated mice, most of the behavioral signs and the overall score of naloxone-precipitated withdrawal were largely diminished in EphB1-/-mice compared to those in the wild-type. These findings indicate that the EphB1 receptor is necessary for development of neuropathic pain and physical dependence on morphine and suggest that the EphB1 receptor is a potential target for preventing, minimizing, or reversing the development of neuropathic pain and opiate dependence.

Background: Long-term potentiation (LTP), a much studied cellular model of synaptic plasticity, has not been demonstrated at synapses between primary afferent C-fibers and spinal dorsal horn (DH) neurons in mice in vivo. EphrinB-EphB receptor signaling plays important roles in synaptic connection and plasticity in the nervous system, but its role in spinal synaptic plasticity remains unclear.