Pain

Publications in this journal

• Article: New pieces for the substance P puzzle.

  Clas Linnman
  Pain 04/2013;
• Article: Chronic pain and cognitive function.

  Brian E McGuire
  Pain 04/2013;
• Article: Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice.

  Mona Lisa Chanda, Alexander H Tuttle, Inna Baran, Cori Atlin, Daniella Guindi, Georgia Hathaway, Nyrie Israelian, Jeremy Levenstadt, Daniel Low, Lynn Macrae, Louise O'Shea, Alex Silver, Elaina Zendegui, A Mariette Lenselink, Sabine Spijker, Michel D Ferrari, Arn M J M van den Maagdenberg, Jeffrey S Mogil
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  ABSTRACT: Migraine is a highly prevalent, disabling and complex episodic brain disorder whose pathogenesis is poorly understood, due in part to the lack of valid animal models. Here we report behavioral evidence of hallmark migraine features, photophobia and unilateral head pain, in transgenic knock-in mice bearing human familial hemiplegic migraine, type 1 (FHM-1) gain-of-function missense mutations (R192Q or S218L) in the Cacna1a gene encoding the CaV2.1 calcium channel α1 subunit. Photophobia was demonstrated using a modified elevated plus maze in which the safe closed arms were brightly illuminated; mutant mice avoided the light despite showing no differences in the standard (anxiety) version of the test. Multiple behavioral measures suggestive of spontaneous head pain were found in 192Q mutants subjected to novelty and/or restraint stress. These behaviors were: (1) more frequent in mutant versus wildtype mice; (2) lateralized in mutant but not in wildtype mice; (3) more frequent in females versus males; and (4) dose-dependently normalized by systemic administration of 2 different acute analgesics, rizatriptan and morphine. Furthermore, some of these behaviors were found to be more frequent and severe in 218L compared to 192Q mutants, consistent with the clinical presentation in humans. We suggest that Cacna1a transgenic mice can experience migraine-related head pain and can thus serve as unique tools to study the pathogenesis of migraine and test novel antimigraine agents.
  Pain 04/2013;
• Article: Natural course of acute neck and low back pain in the general population: The HUNT study.

  Ottar Vasseljen, Astrid Woodhouse, Johan Håkon Bjørngaard, Linda Leivseth
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  ABSTRACT: In this prospective cohort study we aimed to describe the natural course of acute neck and low back pain in a general population of Norway. We screened 9056 subjects aged 20-67years who participated in a general health survey for a new episode of neck or low back pain the previous month. The screening identified 219 subjects who formed the cohort for this study. Pain intensity was reported on a numeric rating scale (0-10) at 1, 2, 3, 6, and 12months after start of the new pain episode. The course of pain was described for neck and low back pain, different baseline pain levels, age groups, and number of pain sites at baseline. Use of medication and health care was described and associations between pain intensity and seeking health care were estimated. Pain declined rapidly within 1month after a new pain episode, with a reduction of 0.91 (95% confidence interval [CI] 0.50-1.32) for neck pain and 1.40 (95% CI 0.82-1.99) for low back pain with little change thereafter. However, pain remained unchanged over the follow-up year for those with equal pain in the neck and low back areas at baseline and for those reporting 4 or more pain sites at baseline. Only 1 in 5 sought health care for their complaints. Still, the course of pain was comparable to effect sizes reported in interventional studies. This study thus contributes natural course reference data for comparisons of pain outcome in clinical trials and practice.
  Pain 04/2013;
• Article: The role of circulating sex hormones in menstrual cycle-dependent modulation of pain-related brain activation.

  Dieuwke S Veldhuijzen, Michael L Keaser, Deborah S Traub, Jiachen Zhuo, Rao P Gullapalli, Joel D Greenspan
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  ABSTRACT: Sex differences in pain sensitivity have been consistently found, but the basis for these differences is incompletely understood. The present study assessed how pain-related neural processing varies across the menstrual cycle in normally cycling, healthy women, and whether menstrual cycle effects are based on fluctuating sex hormone levels. Fifteen subjects participated in 4 test sessions during their menstrual, midfollicular, ovulatory, and midluteal phases. Brain activity was measured while nonpainful and painful stimuli were applied with a pressure algometer. Serum hormone levels confirmed that scans were performed at appropriate cycle phases in 14 subjects. No significant cycle phase differences were found for pain intensity or unpleasantness ratings of stimuli applied during functional magnetic resonance imaging scans. However, lower pressure pain thresholds were found for follicular compared with other phases. Pain-specific brain activation was found in several regions traditionally associated with pain processing, including the medial thalamus, anterior and middle insula, midcingulate, primary and secondary somatosensory cortices, cerebellum, and frontal regions. The inferior parietal lobule, occipital gyrus, cerebellum, and several frontal regions showed interaction effects between stimulus level and cycle phase, indicating differential processing of pain-related responses across menstrual cycle phases. Correlational analyses indicated that cycle-related changes in pain sensitivity measures and brain activation were only partly explained by varying sex hormone levels. These results show that pain-related cerebral activation varies significantly across the menstrual cycle, even when perceived pain intensity and unpleasantness remain constant. The involved brain regions suggest that cognitive pain or more general bodily awareness systems are most susceptible to menstrual cycle effects.
  Pain 04/2013; 154(4):548-59.
• Article: Hypnotic susceptibility modulates brain activity related to experimental placebo analgesia.

  Alexa Huber, Fausta Lui, Carlo Adolfo Porro
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  ABSTRACT: Identifying personality traits and neural signatures that predict placebo responsiveness is important, both on theoretical and practical grounds. In the present functional magnetic resonance imaging (fMRI) study, we performed multiple-regression interaction analysis to investigate whether hypnotic susceptibility (HS), a cognitive trait referring to the responsiveness to suggestions, explains interindividual differences in the neural mechanisms related to conditioned placebo analgesia in healthy volunteers. HS was not related to the overall strength of placebo analgesia. However, we found several HS-related differences in the patterns of fMRI activity and seed-based functional connectivity that accompanied placebo analgesia. Specifically, in subjects with higher HS, the placebo response was related to increased anticipatory activity in a right dorsolateral prefrontal cortex focus, and to reduced functional connectivity of that focus with brain regions related to emotional and evaluative pain processing (anterior mid-cingulate cortex/medial prefrontal cortex); an opposite pattern of fMRI activity and functional connectivity was found in subjects with lower HS. During pain perception, activity in the regions reflecting attention/arousal (bilateral anterior thalamus/left caudate) and self-related processing (left precuneus and bilateral posterior temporal foci) was negatively related to the strength of the analgesic placebo response in subjects with higher HS, but not in subjects with lower HS. These findings highlight HS influences on brain circuits related to the placebo analgesic effects. More generally, they demonstrate that different neural mechanisms can be involved in placebo responsiveness, depending on individual cognitive traits.
  Pain 03/2013;
• Article: Deficits in glycinergic inhibition within adult spinal nociceptive circuits after neonatal tissue damage.

  Jie Li, Meredith L Blankenship, Mark L Baccei
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  ABSTRACT: Tissue injury during a critical period of early postnatal development can alter pain sensitivity throughout life. However, the degree to which neonatal tissue damage exerts prolonged effects on synaptic signaling within adult spinal nociceptive circuits remains unknown. Here we provide evidence that a transient surgical injury of the hind paw during the neonatal period compromises inhibitory transmission within the adult mouse superficial dorsal horn (SDH), while the same incision occurring during the third week of life failed to evoke these long-term modifications of the SDH synaptic network. The decrease in phasic inhibitory signaling after early tissue damage reflected a selective reduction in glycine receptor (GlyR)-mediated input onto both GABAergic and presumed glutamatergic neurons within lamina II of the adult SDH. Meanwhile, neonatal incision significantly decreased the density of tonic GlyR-mediated current only in the presumed glutamatergic population during adulthood. These persistent changes in synaptic function following early injury occurred in the absence of significant alterations in the transcription of genes known to be important for glycinergic transmission. These findings suggest that aberrant sensory input during early life has permanent consequences for the functional organization of nociceptive synaptic circuits within the adult spinal cord.
  Pain 03/2013;
• Article: Inhibition of IL-6 signaling: A novel therapeutic approach to treating spinal cord injury pain.

  Jutatip Guptarak, Sheshali Wanchoo, Julieann Durham-Lee, Yewen Wu, Dragoslava Zivadinovic, Adriana Paulucci-Holthauzen, Olivera Nesic
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  ABSTRACT: To characterize the contribution of interleukin-6 (IL-6) to spinal cord injury pain (SCIP), we employed a clinically relevant rat contusion model of SCIP. Using Western blots, we measured IL-6 levels in lumbar segments (L1-L5), at the lesion site (T10), and in the corresponding lumbar and thoracic dorsal root ganglia (DRG) in 2 groups of similarly injured rats: (a) SCI rats that developed hind-limb mechanical allodynia (SCIP), and (b) SCI rats that did not develop SCIP. Only in SCIP rats did we find significantly increased IL-6 levels. Immunocytochemistry showed elevated IL-6 predominantly in reactive astrocytes. Our data also showed that increased production of IL-6 in hyperreactive astrocytes in SCIP rats may explain still-poorly understood astrocytic contribution to SCIP. To test the hypothesis that IL-6 contributes to mechanical allodynia, we treated SCIP rats with neutralizing IL-6 receptor antibody (IL-6-R Ab), and found that one systemic injection abolished allodynia and associated weight loss; in contrast to gabapentin, the analgesic effect lasted for at least 2weeks after the injection, despite the shorter presence of the Ab in the circulation. We also showed that IL-6-R Ab partially reversed SCI-induced decreases in the protein levels of the glutamate transporter GLT-1 12hours and 8days after Ab injection, which may explain the lasting analgesic effect of the Ab in SCIP rats. A link between reactive astrocytes IL-6-GLT-1 has not been previously shown. Given that the humanized IL-6-R Ab tocilizumab is Food and Drug Administration-approved for rheumatoid arthritis, we are proposing tocilizumab as a novel and potentially effective treatment for SCIP.
  Pain 03/2013;
• Article: Response to the Letter to the Editor of Pain by S. Canavero.

  Charles J Vierck, Barry L Whitsel, Oleg V Favorov, Mark Tommerdahl
  Pain 03/2013;
• Article: Emotional modulation of pain and spinal nociception in fibromyalgia.

  Jamie L Rhudy, Jennifer L Delventura, Ellen L Terry, Emily J Bartley, Ewa Olech, Shreela Palit, Kara L Kerr
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  ABSTRACT: Fibromyalgia (FM) is characterized by widespread pain, as well as affective disturbance (eg, depression). Given that emotional processes are known to modulate pain, a disruption of emotion and emotional modulation of pain and nociception may contribute to FM. The present study used a well-validated affective picture-viewing paradigm to study emotional processing and emotional modulation of pain and spinal nociception. Participants were 18 individuals with FM, 18 individuals with rheumatoid arthritis (RA), and 19 healthy pain-free controls (HC). Mutilation, neutral, and erotic pictures were presented in 4 blocks; 2 blocks assessed only physiological-emotional reactions (ie, pleasure/arousal ratings, corrugator electromyography, startle modulation, skin conductance) in the absence of pain, and 2 blocks assessed emotional reactivity and emotional modulation of pain and the nociceptive flexion reflex (NFR, a physiological measure of spinal nociception) evoked by suprathreshold electric stimulations over the sural nerve. In general, mutilation pictures elicited displeasure, corrugator activity, subjective arousal, and sympathetic activation, whereas erotic pictures elicited pleasure, subjective arousal, and sympathetic activation. However, FM was associated with deficits in appetitive activation (eg, reduced pleasure/arousal to erotica). Moreover, emotional modulation of pain was observed in HC and RA, but not FM, even though all 3 groups evidenced modulation of NFR. Additionally, NFR thresholds were not lower in the FM group, indicating a lack of spinal sensitization. Together, these results suggest that FM is associated with a disruption of supraspinal processes associated with positive affect and emotional modulation of pain, but not brain-to-spinal cord circuitry that modulates spinal nociceptive processes.
  Pain 03/2013;
• Article: Smoking as a risk factor for chronic musculoskeletal complaints is influenced by age. The HUNT Study.

  Synnøve Kvalheim, Irene Sandven, Knut Hagen, John-Anker Zwart
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  ABSTRACT: Chronic musculoskeletal complaints (MSCs) are among the major health problems, and cross-sectional studies suggest an association between smoking and MSCs. The causal relationship, however, is not known. The present study is designed to assess the association between smoking and chronic MSCs, and is based on data from a large longitudinal cohort study of all inhabitants ⩾20years in Nord-Trøndelag County (Helse Undersøkelsen i Nord-Trøndelag -HUNT), conducted in 1995-97 (HUNT 2) and 2006-08 (HUNT 3). The study population consisted of 15,134 subjects without chronic MSCs and valid exposure data on smoking at baseline (HUNT 2). The outcome was defined as presence of chronic MSCs at follow-up (HUNT 3). The results show that smoking at baseline represents a 20% increased risk (IRR=1.20, 95% CI 1.14-1.27, P=0.0001) for chronic MSCs at follow-up. The risk for chronic MSCs by daily smoking decreased with increasing age up to 50years; after this, there was no significant association. The results show that modifiable risk factors like smoking should be included in public health intervention programs for MSCs.
  Pain 03/2013;
• Article: Alterations in endogenous pain modulation in endurance athletes: An experimental study using quantitative sensory testing and the cold-pressor task.

  Jonas Tesarz, Andreas Gerhardt, Kai Schommer, Rolf-Detlef Treede, Wolfgang Eich
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  ABSTRACT: There is evidence for long-term alterations in pain tolerance among athletes compared with normally active controls. However, scientific data on pain thresholds in this population are inconsistent, and the underlying mechanisms for the differences remain unclear. Therefore, we assessed differences and similarities in pain perception and conditioned pain modulation (CPM) at rest in endurance athletes and normally active controls. The standardised quantitative sensory testing protocol (QST) of the 'German-Research-Network-on-Neuropathic-Pain' was used to obtain comprehensive profiles on somatosensory functions. The protocol consisted of thermal and mechanical detection as well as pain thresholds, vibration thresholds, and pain sensitivity to sharp and blunt mechanical stimuli. CPM (the diffuse-noxious-inhibitory-control-like effect) was measured using 2 tonic heat pain test stimuli (at the temperature exceeding a subjective pain rating of 50/100) separated by a 2-min cold-pressor task (CPM-TASK; conditioning stimulus). Pain ratings were measured with a numerical rating scale. Endurance capacity was validated by assessment of maximum oxygen uptake (VO2max). Participants included 25 pain-free male endurance athletes (VO2max>60mL/min∗kg) and 26 pain-free normally active controls (VO2max<45mL/min∗kg) matched based on age and body mass index. Athletes were significantly less sensitive to mechanical pain but showed higher sensitivity to vibration (P<0.05). In athletes, CPM was significantly less activated by the conditioning stimuli (P<0.05) when compared with normally active controls. Our data show that somatosensory processing in athletes differs in comparison with controls, and suggest that the endogenous pain inhibitory system may be less responsive. This finding may explain the paradoxical propensity of athletes to develop chronic widespread pain.
  Pain 03/2013;
• Article: Endocannabinoids: A unique opportunity to develop multitarget analgesics.

  Sabatino Maione, Barbara Costa, Vincenzo Di Marzo
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  ABSTRACT: After 4 millennia of more or less documented history of cannabis use, the identification of cannabinoids, and of Δ(9)-tetrahydrocannabinol in particular, occurred only during the early 1960s, and the cloning of cannabinoid CB1 and CB2 receptors, as well as the discovery of endocannabinoids and their metabolic enzymes, in the 1990s. Despite this initial relatively slow progress of cannabinoid research, the turn of the century marked an incredible acceleration in discoveries on the "endocannabinoid signaling system," its role in physiological and pathological conditions, and pain in particular, its pharmacological targeting with selective agonists, antagonists, and inhibitors of metabolism, and its previously unsuspected complexity. The way researchers look at this system has thus rapidly evolved towards the idea of the "endocannabinoidome," that is, a complex system including also several endocannabinoid-like mediators and their often redundant metabolic enzymes and "promiscuous" molecular targets. These peculiar complications of endocannabinoid signaling have not discouraged efforts aiming at its pharmacological manipulation, which, nevertheless, now seems to require the development of multitarget drugs, or the re-visitation of naturally occurring compounds with more than one mechanism of action. In fact, these molecules, as compared to "magic bullets," seem to offer the advantage of modulating the "endocannabinoidome" in a safer and more therapeutically efficacious way. This approach has provided so far promising preclinical results potentially useful for the future efficacious and safe treatment of chronic pain and inflammation.
  Pain 03/2013;
• Article: Effects of motion style acupuncture treatment in acute low back pain patients with severe disability: A multicenter, randomized, controlled, comparative effectiveness trial.

  Joon-Shik Shin, In-Hyuk Ha, Jinho Lee, Youngkwon Choi, Me-Riong Kim, Byoung-Yoon Park, Byung-Cheul Shin, Myeong Soo Lee
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  ABSTRACT: Reviews of the efficacy of acupuncture as a treatment for acute low back pain (aLBP) have shown that there is insufficient evidence for its effect and that more research is needed. Motion style acupuncture treatment (MSAT) is novel in that it requires a part of the patient's body to move passively or actively while acupuncture needles are retained. A multicenter, randomized, comparative effectiveness trial was conducted to evaluate the effects of MSAT in aLBP with severe disability. A total of 58 aLBP patients with severe functional disability (defined per Oswestry Disability Index [ODI] ⩾60%) were recruited and assigned randomly to receive 1 session of either conventional diclofenac injection (n=29) or MSAT (n=29). The primary outcome measured improvement in LBP using the 10-point numerical rating scale of LBP, and the secondary outcome assessed disability using the Oswestry Disability Index at 30minutes and at 2, 4, and 24weeks after treatment. Analyses were by intention to treat. The numerical rating scale of the MSAT group decreased 3.12 (95% confidence interval=2.26, 3.98; P<.0001) more than that of the injection group and the Oswestry Disability Index of the MSAT group decreased 32.95% (95% confidence interval=26.88, 39.03; P<.0001) more than that of the injection group, respectively. The difference between the 2 groups maintained statistical significance at 2 and 4weeks after treatment. These results suggest that MSAT has positive effects on immediate pain relief and the functional recovery of aLBP patients with severe disability.
  Pain 03/2013;
• Article: Disturbances in slow-wave sleep are induced by models of bilateral, inflammation, neuropathic, and postoperative pain, but not osteoarthritic pain in rats.

  Laura J Leys, Katharine L Chu, Jun Xu, Madhavi Pai, He S Yang, Holly M Robb, Michael F Jarvis, Richard J Radek, Steve McGaraughty
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  ABSTRACT: Preclinical assessment of pain has typically relied on measuring animal responses to evoked stimulation. Because of inherent limitations of these assays, there is a need to develop measures of animal pain/discomfort that are objective, not experimentally evoked, and mimic the human condition. Patients with chronic pain manifest a variety of co-morbidities, one of which is disturbances in sleep. We used electroencephalography to objectively assess 4 rat models of pain (inflammatory/complete Freund's adjuvant [CFA], neuropathic/chronic constriction injury [CCI], postoperative/skin incision, osteoarthritis/monosodium iodoacetate [MIA]) for the occurrence of sleep disturbances. Four different measures of slow-wave sleep (SWS) were examined: amplitude of 1- to 4-Hz waves, total time spent in SWS, time spent in SWS-1, and time spent in SWS-2. Bilateral injuries were more likely to induce a sleep disturbance than unilateral injuries in the CFA, CCI, and skin incision assays. Sleep disturbances occurred in the deeper stage of SWS, as the amplitude of 1- to 4-Hz waves and time spent in SWS-2 were significantly decreased in all models except the osteoarthritis model. Sleep disturbances lasted for approximately 3 to 14days, depending on the model, and were resolved despite continued hypersensitivity to evoked stimulation. Morphine, gabapentin, diclofenac, and ABT-102 (TRPV1 antagonist) all improved sleep in the bilateral CFA assay at doses that did not significantly alter SWS in uninjured rats. Preclinical assessment of compounds should follow the path of clinical studies and take into account diverse aspects of the "pain condition." This would include evaluating nociceptive thresholds as well as other endpoints, such as cognition and sleep, that may be affected by the pathological state.
  Pain 03/2013;
• Article: Sensitized pain response to bradykinin after sunburn - a human model for ongoing inflammatory pain?

  Martin Schmelz
  Pain 03/2013;
• Article: Estrogen status and psychophysical stress modify temporomandibular joint input to medullary dorsal horn neurons in a lamina-specific manner in female rats.

  Keiichiro Okamoto, Randall Thompson, Ayano Katagiri, David A Bereiter
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  ABSTRACT: Estrogen status and psychological stress contribute to the expression of several chronic pain conditions including temporomandibular muscle and joint disorders (TMJD). Sensory neurons that supply the temporomandibular joint (TMJ) region terminate in laminae I and V of the spinal trigeminal nucleus (Vc/C1-2 region); however, little is known about lamina-specificity and environmental influences on the encoding properties of TMJ brainstem neurons. To test the hypothesis that Vc/C1-2 neurons integrate both interoceptive and exteroceptive signals relevant for TMJ nociception, we recorded TMJ-evoked activity in superficial and deep laminae of ovariectomized rats under high and low estradiol (E2) and stress conditions. Rats received daily injections of low (LE) or high (HE) dose E2 and were subjected to forced swim (FS) or sham swim conditioning for 3days. The results revealed marked lamina-specificity in that HE rats displayed enhanced TMJ-evoked activity in superficial, but not deep, laminae independent of stress conditioning. By contrast, FS conditioned rats displayed increased background firing and TMJ-evoked activity of neurons in deep, but not superficial, laminae independent of E2 status. FS also enhanced TMJ-evoked masseter muscle activity and suggested the importance of deep dorsal horn neurons in mediating evoked jaw muscle activity. In conclusion, E2 status and psychophysical stress play a significant role in modifying the encoding properties of TMJ-responsive medullary dorsal horn neurons with a marked lamina-specificity.
  Pain 03/2013;
• Article: mTORC1 inhibition induces pain via IRS-1-dependent feedback activation of ERK.

  Ohannes K Melemedjian, Arkady Khoutorsky, Robert E Sorge, Jin Yan, Marina N Asiedu, Arely Valdez, Sourav Ghosh, Gregory Dussor, Jeffrey S Mogil, Nahum Sonenberg, Theodore J Price
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  ABSTRACT: Mammalian target of rapamycin complex 1 (mTORC1) inhibitors are extensively used as immunosuppressants to prevent transplant rejection and in treatment of certain cancers. In patients, chronic treatment with rapamycin or its analogues (rapalogues) has been reported to lead to sensory hypersensitivity and pain conditions via an unknown mechanism. Here, we show that pharmacological or genetic inhibition of mTORC1 activates the extracellular signal-regulated kinase (ERK) pathway in sensory neurons via suppression of S6K1 to insulin receptor substrate 1 negative feedback loop. As a result, increased ERK activity induces sensory neuron sensitization, mechanical hypersensitivity, and spontaneous pain. The clinically available adenosine monophosphate-activated protein kinase activator, metformin, which is an antidiabetic drug, prevents rapamycin-induced ERK activation and the development of mechanical hypersensitivity and spontaneous pain. Taken together, our findings demonstrate that activation of the ERK pathway in sensory neurons as a consequence of mTORC1 inhibition leads to the development of pain. Importantly, this effect is abolished by co-treatment with metformin, thus providing a potential treatment option for rapalogue-evoked pain. Our findings highlight the physiological relevance of feedback signaling through mTORC1 inhibition and have important implications for development of pain therapeutics that target the mTOR pathway.
  Pain 03/2013;
• Article: Musculoskeletal pain in different occupational groups and different countries.

  Sebastian Straube, Peter Croft
  Pain 03/2013;