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Quantitative sensory testing (QST) is used to systematically interrogate normal responding and alterations of nervous system function, including pain related central sensitization (CS). However, up to now QST of CS in human subjects has been mostly focused on temporal summation of second pain (TSSP), has been difficult to perform, and has been associated with low reliability. In contrast, slow ramp & hold (RH) procedures are simpler tests of temporal summation and easier to perform. We examined the usefulness of RH procedures as reliable generators of CS using two validated QST procedures: decay of pain aftersensations and wind-down. Twenty-seven pain-free subjects (74% female) were enrolled into the study. Trains of sensitivity adjusted TSSP or RH heat stimuli were applied to the hands of participants to achieve moderate temporal pain summation [50 NRS (0-100)]. Fifteen second aftersensations and 30s wind-down related to TSSP or RH were used for CS comparisons. Reliability of all test procedures was tested over 24 h. Use of sensitivity adjusted TSSP and RH heat stimuli resulted in average pain ratings of 48.2 and 49.6 NRS, respectively. Aftersensations or wind-down decay were not significantly different after either TSSP or RH, (all p > .05), indicating that each procedure achieved similar levels of short-term CS. Sensitivity adjusted RH stimuli were well tolerated and resulted in reliable pain increases of 50 NRS. The magnitude of short-term CS, determined by aftersensations and wind-down was similar after sensitivity-adjusted TSSP and RH stimuli (p > .05), suggesting that pain facilitation of healthy participants and likely chronic pain patients can not only be tested with TSSP but also with RH procedures. Perspective: This article examines the ability of RH procedures to generate similar central sensitivity augmentation than TSSP. The results suggest that RH is similarly well suited as TSSP to explore central pain mechanisms in healthy subjects and most likely also in chronic pain patients.
Learn More >The classification of chronic visceral pain is complex, resulting from persistent inflammation, vascular (ischemic) mechanisms, cancer, obstruction or distension, traction or compression, and combined mechanisms, as well as unexplained functional mechanisms. Despite the prevalence, treatment options for chronic visceral pain are limited. Given this unmet clinical need, the development of novel analgesic agents, with defined targets derived from preclinical studies, is urgently needed. While various animal models have played an important role in our understanding of visceral pain, our knowledge is far from complete. Due to the complexity of visceral pain, this document will focus on chronic abdominal pain, which is the major complaint in patients with disorders of the gut-brain interaction, also referred to as functional gastrointestinal disorders, such as irritable bowel syndrome (IBS). Models for IBS are faced with challenges including a complex clinical phenotype, which is comorbid with other conditions including anxiety, depression, painful bladder syndrome, and chronic pelvic pain. Based upon the multifactorial nature of IBS with complicated interactions between biological, psychological, and sociological variables, no single experimental model recapitulates all the symptoms of IBS. This position paper will contextualize chronic visceral pain using the example of IBS and focus on its pathophysiology while providing a critical review of current animal models that are most relevant, robust, and reliable in which to screen promising therapeutics to alleviate visceral pain and delineate the gaps and challenges with these models. We will also highlight, prioritize, and come to a consensus on the models with the highest face/construct validity.
Learn More >Mechanical injury is the most important risk factor in osteoarthritis (OA) development. Although once considered a passive disease of mechanical attrition, injury drives active mechanosensitive intracellular signalling which affects the structural and symptomatic course of disease. Mechanosensitive signalling in cartilage has been elucidated over the years and two principal responses emerge: those that cause the release of growth factors from the matrix and which stimulate repair, and those that drive inflammatory signalling, a process that we have termed "mechanoflammation". The up-stream activator of mechanoflammation remains unknown, but it results in rapid activation of NFkB and the inflammatory mitogen activated protein (MAP) kinases and this controls the bioavailability of aggrecanase and regulation of nerve growth factor (NGF), causing pain. The precise relationship between mechanoflammation and cartilage repair is currently unclear but it is likely that chronic mechanoflammation will contribute to disease by also suppressing intrinisic tissue repair.
Learn More >In this chapter, we provide an overview of neuroimaging studies in chronic pain. We start with an introduction about the phenomenology of pain. In the following section, the application of functional and structural imaging techniques is shown in selected chronic pain syndromes (chronic back pain, fibromyalgia syndrome (FMS), phantom limb pain, and complex regional pain syndrome (CRPS)), and commonalities and peculiarities of imaging correlates across different types of chronic pain are discussed. We conclude this chapter with implications for treatments, with focus on behavioral interventions, sensory and motor trainings, and mirror and motor imagery trainings.
Learn More >The flavoring agent menthol elicits complex orosensory and behavioral effects including perceived cooling at low concentrations, and irritation and ingestive avoidance at higher intensities. Oral menthol engages the cold-activated transient receptor potential (TRP) ion channel TRP melastatin 8 (TRPM8) on trigeminal fibers, although its aversive feature was discussed to involve activation of TRP ankyrin 1 (TRPA1) associated with nociceptive processing. Here we studied the roles of TRPM8 and TRPA1 in orosensory responding to menthol by subjecting mice gene-deficient for either channel to brief-access exposure tests, which measure immediate licking responses to fluid stimuli to capture sensory/tongue control of behavior. Stimuli included aqueous concentration series of (-)-menthol (0 [water], 0.3, 0.5, 0.7, 1.0, 1.5, and 2.3 mM) and the aversive bitter taste stimulus quinine-HCl (0, 0.01, 0.03, 0.1, 0.3, 1, and 3 mM). Concentration-response data were generated from daily brief-access tests conducted in lickometers, which recorded the number of licks water-restricted mice emitted to a randomly selected stimulus concentration over a block of several 10 sec stimulus presentations. Wild-type mice showed aversive orosensory responses to menthol above 0.7 mM. Oral aversion to menthol was reduced in mice deficient for TRPA1, but not TRPM8. Oral aversion to quinine was similar between TRPA1 mutant and control mice but stronger than avoidance of menthol. This implied menthol avoidance under the present conditions represented a moderate form of oral aversion. These data reveal TRPA1 contributes to the oral sensory valence of menthol and have implications for how input from TRPA1 and TRPM8 shapes somatosensory-guided behaviors. Menthol is used in confectionery, tobacco, and oral consumer products to add a pleasant "coolness" to their flavor appeal. Yet menthol's sensation is complex and includes coolness at low but irritation at high concentrations. Elucidating mechanisms that underlie menthol's aversive flavor component would facilitate understanding of how trigeminal circuits distinguish noxious from innocuous stimuli. Although engaging the cold receptor TRPM8, menthol was discussed to induce oral irritation through its activation of TRPA1, which is expressed on nociceptive fibers usually devoid of TRPM8. Here we found mice gene-deficient for TRPA1, but not TRPM8, show reduced aversion to menthol in an oral sensory-guided behavioral task. These results have implications for how TRPM8 and TRPA1 afferents contribute to hedonic tone during somatosensory-influenced behaviors.
Learn More >The main aim of this work was to identify and to share the lessons learned from the negative outcome of the mirogabalin ALDAY phase 3 clinical program in pain associated with fibromyalgia. These lessons are important to improve planning and design of future phase 3 programs in fibromyalgia. A systematic review from Cochrane Library, Medline, Embase, clinicaltrials.gov, pharmaceutical companies and regulatory agencies' websites, was carried out starting from the development of gabapentin, the first α2δ ligand studied for the treatment of neuropathic pain and ending with the mirogabalin program. Based on the outcome of the main fibromyalgia programs, several differences in design, primary endpoint choice, magnitude of placebo response, presence of an active comparator, and size of the entire clinical program were identified. This analysis focused on the negative primary results of the mirogabalin ALDAY program and identified several contributing factors. Above all, the magnitude of placebo response and the unprecedented size of the program were identified. The number of study visits and procedures was also high and highly demanding for all subjects involved in ALDAY. In terms of main lessons learned from ALDAY, the first was the need for a comprehensive patient-focused strategy to preliminarily identify the challenges of fibromyalgia based on patient perspective and study complexity. Second, there was a need for a harmonized, truly patient-centric, global regulatory guidance accepted by regulatory agencies. Third, ALDAY proved that a phase 2 proof of concept, dose ranging study is necessary before commencing any phase 3 program in fibromyalgia.
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