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The main cause of trigeminal neuralgia (TN) is compression of a blood vessel at the root entry zone of the trigeminal nerve. However, a neurovascular conflict does not seem to be the only etiology and other mechanisms are implicated in the development of the disease. We hypothesized that TN patients may have distinct protein expression in the CSF. In this study, lumbar CSF from TN patients (n=17), scheduled to undergo microvascular decompression (MVD), and from controls (n=20) was analyzed and compared with mass spectrometry-based shotgun proteomics. 2552 unique proteins were identified of which 46 were significantly altered (26 increased, and 20 decreased, q-value < 0.05) in TN patients compared with controls. An over-representation analysis showed proteins involved in high-density lipoprotein (HDL), such as APOA-4, APOM and APOA-1, and the extracellular region, including proteins involved in the complement cascade to be over-represented. We conclude that TN patients have distinct protein expression in the CSF compared to controls. The pathophysiological background of the protein alterations found in this study warrants further investigation in future studies. Perspective: In this article, cerebrospinal fluid from patients with trigeminal neuralgia was analyzed using in depth shotgun proteomics, revealing 46 differentially expressed proteins compared to controls. Among these, apolipoproteins and proteins involved in the complement system were elevated and significantly over-represented, implying an inflammatory component in the pathophysiology of the disease.
Learn More >In exposure for chronic pain, avoidance is often forbidden (extinction with response prevention; RPE) to prevent misattributions of safety. Although exposure is an effective treatment, relapse is common. Little is known about the underlying mechanisms of return of pain-related avoidance. We hypothesized that pain-related avoidance would recover when becoming available again after RPE and after unexpected pain episodes ("reinstatement"), especially when restricting avoidance during RPE (compared to instructing not to use it). In an operant pain-related avoidance conditioning paradigm, healthy volunteers used a robotic arm to perform various arm reaching movements differing in pain-effort trade-off. During acquisition, participants learned to avoid pain by performing more effortful movements. During RPE they only performed the formerly pain-associated movement under extinction, and were either forbidden (Restricted group) or merely instructed (Instructed group) not to perform other movements. One day later, we tested spontaneous recovery and reinstatement of pain-related fear and avoidance with availability of all movements. Results showed that pain-related fear and avoidance re-emerge after RPE, though not to pre-treatment levels. The reinstatement manipulation had no additional effect. No group differences were observed. We discuss findings in the context of learning processes in (chronic) pain disability and relapse prevention in chronic pain treatment. Perspective: Using experimental models of relapse, we investigated the return of pain-related avoidance behaviour after extinction with response prevention. Findings are potentially informative for clinicians performing exposure treatment with chronic pain patients.
Learn More >Acute and chronic pain delay recovery and impair outcomes after major pediatric surgery. Understanding unique risk factors for acute and chronic pain is critical to developing effective treatments for youth at risk. We aimed to identify adolescent and family psychosocial predictors of acute and chronic postsurgical pain following major surgery in adolescents. Participants included 119 youth age 10-18 years (M=14.9;78.2% white) undergoing major musculoskeletal surgery and their parents. Participants completed pre-surgery baseline questionnaires, with youth reporting on baseline pain, anxiety, depression, insomnia and sleep quality, and parents reporting on parental catastrophizing and family functioning. At baseline, 2-weeks, and 4-months post-surgery, youth completed 7-days of daily pain diaries and reported on health-related quality of life. Sequential logistic regression models examined pre-surgery predictors of acute and chronic postsurgical pain, defined as significant pain with impairment in health-related quality of life. Acute pain was experienced by 27.2% of youth at 2-weeks, while 19.8% of youth met criteria for chronic pain at 4-months. Baseline pain predicted acute pain (OR=1.96; 95%CI=1.32-2.90), while depressive symptoms (OR=1.22; 95%CI=1.01-1.47) and sleep quality (OR=0.26; 95%CI=0.08-0.83) predicted chronic pain. Tailored interventions need to be developed and incorporated into perioperative care to address risk factors for acute and chronic pain. Perspective: Longitudinal results demonstrate adolescents' pre-surgery pain severity predicts acute postsurgical pain, while depressive symptoms and poor sleep quality predict chronic postsurgical pain. Tailored interventions should address separate risk factors for acute and chronic pain after adolescent surgery.
Learn More >A challenge in understanding chronic musculoskeletal pain is that research is often siloed between neuroscience, physical therapy/rehabilitation, orthopedics and rheumatology which focus respectively on 1) neurally-mediated effects on pain processes, 2) behavior and muscle activity, 3) tissue structure and 4) inflammatory processes. Although these disciplines individually study important aspects of pain, there is a need for more cross-disciplinary research that can bridge between them. Identifying the gaps in knowledge is important to understand the whole body, especially at the interfaces between the silos-between brain function and behavior, between behavior and tissue structure, between musculoskeletal and immune systems, and between peripheral tissues and the nervous system. Research on "mind and body" practices can bridge across these silos and encourage a "whole person" approach to better understand musculoskeletal pain by bringing together the brain and the rest of the body. Perspective: Research on chronic musculoskeletal pain is limited by significant knowledge gaps. To be fully integrated, musculoskeletal pain research will need to bridge across tissues, anatomical areas, and body systems. Research on mind and body approaches encourages a "whole person" approach to better understand musculoskeletal pain.
Learn More >Avoidance behavior is protective, yet in the absence of genuine bodily threat, it may become disabling. Therefore, we investigated whether avoidance generalizes to novel safe contexts based on the similarity with the acquisition context. Healthy participants performed arm movements using a robotic arm to reach a target. Three trajectories (T1-3) led to the target. During acquisition, a painful stimulus could be partly/completely prevented by performing more effortful trajectories (i.e. longer and more force needed), T2/T3, in the pain-avoidance context (e.g. black background); in the yoked context (e.g. white background), the same reinforcement schedule was applied irrespective of the chosen trajectories. Generalization of avoidance was tested in two novel contexts (e.g. shades of grey backgrounds). We assessed self-reported pain-expectancy and pain-related fear for all trajectories, and avoidance behavior (i.e. maximal deviation from T1). Results confirm that fear and expectancy ratings reflect the response-outcome contingencies and differential learning selectively generalized to the novel context resembling the original pain-avoidance context. Furthermore, a linear trend in avoidance behavior across contexts emerged, which is indicative of a generalization gradient. Participants avoided more in the context resembling the original pain-avoidance context than in the one resembling the yoked context, but this effect was not statistically significant. PERSPECTIVE: We demonstrated acquisition of pain-related avoidance behavior in a within-subjects design, showing modulation of pain-related fear and pain-expectancy by context and providing limited evidence that avoidance selectively generalizes to novel, similar contexts. These results provide insight regarding the underlying mechanisms of the spreading of protective behavior in chronic pain patients.
Learn More >Serotonin (5-hydroxytryptamine, 5-HT) released by platelets, mast cells, and immunocytes is a potent inflammatory mediator which modulates pain and itch sensing in the peripheral nervous system. The serotonergic receptors expressed by primary afferent neurons involved in these sensory functions are not fully identified and appear to be to a large extent species dependent. Moreover, the mechanisms through which 5-HT receptor activation is coupled to changes in neuronal excitability have not been completely revealed. Using a combination of in vitro (calcium and voltage imaging and patch-clamp) and in vivo behavioral methods, we used both male and female Wistar rats to provide evidence for the involvement of two 5-HT receptor subtypes, 5-HT1A and 5-HT3, in mediating the sustained and transient effects, respectively, of 5-HT on rat primary afferent neurons involved in pain and itch processing. In addition, our results are consistent with a model in which sustained serotonergic responses triggered via the 5-HT1A receptor are due to closure of background potassium channels, followed by membrane depolarization and action potentials, during which the activation of voltage-gated calcium channels leads to calcium entry. Our results may provide a better understanding of mammalian serotonergic itch signaling.
Learn More >Transcranial direct current stimulation was suggested to provide beneficial effects in chronic migraine, a condition often associated with medication overuse for which no long-term therapy is available.
Learn More >Although support provision by a partner is an important resource for individuals with chronic pain (ICPs), it poses a challenge for partners because it competes with other important personal goals of partners. The current study examined the impact of experimentally induced goal conflict in partners on their motives for helping, quality of provided help, and on partners' and ICPs' affect. Sixty-eight couples, with at least one person having chronic pain, performed two series of household activities, with partners either asked to be simply available for help (i.e., control condition) or to additionally work on a puzzle task (i.e., goal conflict condition). Couples reported on interpersonal (e.g., helping motives) and intrapersonal (e.g., affect) outcomes. In addition, quality of partners' helping behavior and ICPs' pain behavior were videotaped and coded afterwards. In the goal conflict condition, ICPs were less satisfied with the received help and they experienced more pain. Also, the quality of the provided help was lower and partners experienced less positive and more negative affect. Addressing partners' goal conflict in clinical practice may help to avoid its negative impact on both ICPs and partners. Perspective: This article provides a compelling argument to include partners in chronic pain treatment by demonstrating the detrimental effects of partners' experienced conflicts in goals upon the quality of help they provide, partners' affective functioning and ICPs' pain-related outcomes.
Learn More >Endothelin-1 (EDN1) can evoke histamine-independent pruritus in mammals and is upregulated in the lesional epidermis of atopic dermatitis (AD). EDN1 increases the production of interleukin 25 (IL-25) from keratinocytes to accelerate T helper type 2 immune deviation. Plasma EDN1 levels are positively correlated with the clinical severity and itch intensity of AD. Therefore, we hypothesized that the inhibition of EDN1 might be useful for treating atopic inflammation and itch and investigated the effects of the topical application of the EDN1 receptor antagonist bosentan on the skin inflammation and itch in a murine AD model.
Learn More >At least one third of HIV-1-afflicted individuals experience peripheral neuropathy. Although the underlying mechanisms are not known, they may involve neurotoxic HIV-1 proteins. We assessed the influence of the neurotoxic HIV-1 regulatory protein, Tat, on inflammatory and neuropathic nociceptive behaviors using transgenic male and female transgenic mice that conditionally expressed (or did not express) HIV-1 Tat in glial fibrillary acidic protein-expressing glia in the central and peripheral nervous systems. Tat induction significantly attenuated the time spent paw-licking following formalin injection (2.5%, i.pl.) in both male and female mice. However, significant sex differences were observed in the onset and magnitude of inflammation and sensory sensitivity following complete Freund's adjuvant (CFA) injection (10%, i.pl.) after Tat activation. Unlike female mice, males showed a significant attenuation of paw swelling and an absence of mechanical/thermal hypersensitivity in response to CFA after Tat induction. Male Tat(+) mice also showed accelerated recovery from chronic constrictive nerve injury (CCI)-induced neuropathic mechanical and thermal hypersensitivity compared to female Tat(+) mice. Morphine (3.2 mg/kg) fully reversed CCI-induced mechanical hypersensitivity in female Tat(-) mice, but not in Tat(+) females. The ability of Tat to decrease edema, paw swelling, and limit allodynia suggest a sequela of events in which Tat-induced functional deficits precede the onset of mechanical hypersensitivity. Moreover, HIV-1 Tat attenuated responses to inflammatory and neuropathic insults in a sex-dependent manner. HIV-1 Tat appears to directly contribute to HIV sensory neuropathy and reveals sex differences in HIV responsiveness and/or the underlying peripheral neuroinflammatory and nociceptive mechanisms.
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