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Neurostimulation therapies are frequently used in patients with chronic pain conditions. They emerged from Gate Control Theory (GCT), which posits that Aβ-fiber activation recruits superficial dorsal horn (SDH) inhibitory networks to "close the gate" on nociceptive transmission, resulting in pain relief. However, the efficacy of current therapies is limited, and the underlying circuits remain poorly understood. For example, it remains unknown whether ongoing stimulation of Aβ-fibers is sufficient to drive activity in SDH neurons. We used multiphoton microscopy in spinal cords extracted from mice expressing the genetically encoded calcium indicator GCaMP6s in glutamatergic and GABAergic populations; activity levels were inferred from deconvolved calcium signals using CaImAn software. Sustained Aβ-fiber stimulation at the dorsal columns or dorsal roots drove robust yet transient activation of both SDH populations. Following the initial increase, activity levels decreased below baseline in glutamatergic neurons and were depressed after stimulation ceased in both populations. Surprisingly, only about half of GABAergic neurons responded to Aβ-fiber stimulation. This subset showed elevated activity for the entire duration of stimulation, while non-responders decreased with time. Our findings suggest that Aβ-fiber stimulation initially recruits both excitatory and inhibitory populations but has divergent effects on their activity, providing a foundation for understanding the analgesic effects of neurostimulation devices.
Learn More >Many patients experience positive symptoms after traumatic nerve injury. Despite the increasing number of experimental studies in models of peripheral neuropathy and the knowledge acquired, most of these patients lack an effective treatment for their chronic pain. One possible explanation might be that most of the preclinical studies focused on the development of mechanical or thermal allodynia/hyperalgesia, neglecting that most of the patients with peripheral neuropathies complain mostly about spontaneous forms of pains. Here, we summarize the aberrant electrophysiological behavior of peripheral nerve fibers recorded in experimental models, the underlying pathophysiological mechanisms, and their relationship with the symptoms reported by patients. Upon nerve section, axotomized but also intact fibers develop ectopic spontaneous activity. Most interestingly, a proportion of axotomized fibers might present receptive fields in the skin far beyond the site of damage, indicative of a functional cross talk between neuromatose and intact fibers. All these features can be linked with some of the symptoms that neuropathic patients experience. Furthermore, we spotlight the consequence of primary afferents with different patterns of spontaneous discharge on the neural code and its relationship with chronic pain states. With this article, readers will be able to understand the pathophysiological mechanisms that might underlie some of the symptoms that experience neuropathic patients, with a special focus on spontaneous pain.
Learn More >Headache is the first cause of consultation in neurology, and one of the most frequent reasons for consultation in general medicine. Migraine is one of the most common, prevalent, and socioeconomically impactful disabling primary headache disorders. Neuroticism can be conceptualized as a disposition to suffer anxiety and emotional disorders in general. Neuroticism has been associated with various mental and physical disorders (e.g., chronic pain, depression), including migraine. With the aim to explore in depth the relationship between migraine and neuroticism, and contribute to the understanding of this relation in order to provide a better treatment for migraine patients based on a personalized and more comprehensive approach, a scoping review was performed using PubMed, Scopus, and Web of Science. Databases were searched independently by the two researchers, reaching a final set of 18 articles to be included. The search terms were: migraine and neuroticism. Neuroticism seems to be highly prevalent in migraine patients. Findings reveal that migraine patients with comorbid depression and anxiety showed higher levels of neuroticism. Depression has been associated with an increased risk of transformation from episodic to chronic migraine whereas neuroticism might be a mediator factor. Neuroticism also might be a mediator factor between childhood maltreatment and migraine. The revision conducted confirms that: (1) Migraine patients usually have a higher level of neuroticism and vulnerability to negative affect, compared to non-migraineurs and tension-type headache patients. (2) Neuroticism is associated with migraine. Nonetheless, more research is needed to clarify potential moderators of this relationship and the role of neuroticism itself in this disease. This knowledge might be useful in order to promote a better management of negative emotions as part of intervention programs in migraine.
Learn More >This review summarizes the risks and benefits of gabapentinoids (gabapentin and pregabalin) for perioperative pain control and the controversies surrounding their use in a variety of settings. We review current literature with the goal of providing patient-centric and procedure-specific recommendations for the use of these medications.
Learn More >The purpose of this scoping review was to analyze the published literature regarding the use of art in the context of rehabilitation for consideration in physical therapy.
Learn More >Rheumatic diseases are often associated to debilitating chronic pain, which remains difficult to treat and requires new therapeutic strategies. We had previously identified lysophosphatidyl-choline (LPC) in the synovial fluids from few patients, and shown its effect as a positive modulator of Acid-Sensing Ion Channel 3 (ASIC3) able to induce acute cutaneous pain in rodents. However, the possible involvement of LPC in chronic joint pain remained completely unknown. Here we show, from two independent cohorts of patients with painful rheumatic diseases, that the synovial fluid levels of LPC are significantly elevated, especially the LPC16:0 species, compared to post mortem controls. Moreover, LPC16:0 levels are correlated with pain outcomes in a cohort of osteoarthritis (OA) patients. However, LPC16:0 but do not appear to be the hallmark of a particular joint disease, since similar levels are found in the synovial fluids of a second cohort of patients with various rheumatic diseases. The mechanism of action was next explored by developing a pathology-derived rodent model. Intra-articular injections of LPC16:0 is a triggering factor of chronic joint pain in both male and female mice, ultimately leading to persistent pain and anxiety-like behaviors. All these effects are dependent on ASIC3 channels, which drive sufficient peripheral inputs to generate spinal sensitization processes. This study brings evidences from mouse and human supporting a role for LPC16:0 via ASIC3 channels in chronic pain arising from joints, with potential implications for pain management in OA and possibly across other rheumatic diseases.
Learn More >Chronic pain is a pervasive health problem and is associated with tremendous socioeconomic costs. However, current pain treatments are often ineffective due, in part, to the multi-factorial nature of pain. Mild hypohydration was shown to increase experimental pain sensitivity in men, but whether this also occurs in women has not been examined. Fluctuations in ovarian hormones (i.e., 17ß-oestradiol and progesterone) throughout the menstrual cycle may influence a woman's pain sensitivity, as well as hydration levels, suggesting possible interactions between hypohydration and menstrual phase on pain. We investigated the effects of mild hypohydration (HYPO, 24 hr of fluid restriction) on ischaemic pain sensitivity in 14 eumenorrheic women during the early follicular (EF) and mid-luteal (ML) phases of their menstrual cycle. We also examined whether acute water ingestion could reverse the negative effects of hypohydration. Elevated serum osmolality, plasma copeptin, and urine specific gravity indicated mild hypohydration. Compared to euhydration, HYPO reduced pain tolerance (by 34 ± 46 s; P = 0.02, ηp = 0.37) and increased ratings of pain intensity (by 0.7 ± 0.7 cm; P = 0.004; ηp = 0.55) and unpleasantness (by 0.7 ± 0.9 cm; P = 0.02; ηp = 0.40); these results were not influenced by menstrual phase. Water ingestion reduced thirst perception (Visual Analogue Scale, by 2.3 ± 0.9 cm; P < 0.001, ηp = 0.88) but did not reduce pain sensitivity. Therefore, hypohydration increases pain sensitivity in women with no influence of menstrual phase.
Learn More >Depression, anxiety, and chronic pain are common comorbidities in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) and may substantially impact patient outcomes. We aimed to determine whether these comorbidities were associated with earlier TNF-inhibitor (TNFi) discontinuation.
Learn More >Females suffer higher rates of operative recurrence and chronic pain following groin hernia repair. Guidelines recommend minimally invasive (MIS) groin hernia repair as the preferred approach to reduce these adverse outcomes. It is unknown what proportion of females receive MIS hernia repair. Therefore, our goal was to investigate adoption of evidence-based practices in groin hernia repair using sex as a biological variable.
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