The journal of pain : official journal of the American Pain Society
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Macrophages play a role in innate immunity within the body, are located in muscle tissue, and can release inflammatory cytokines that sensitize local nociceptors. In this study we investigate the role of resident macrophages in the noninflammatory muscle pain model induced by 2 pH 4.0 preservative-free sterile saline (pH 4.0) injections 5 days apart in the gastrocnemius muscle. We showed that injecting 2 pH 4.0 injections into the gastrocnemius muscle increased the number of local muscle macrophages, and depleting muscle macrophages with clodronate liposomes before acid injections attenuated the hyperalgesia produced by this model. To further examine the contribution of local macrophages to this hyperalgesia, we injected mice intramuscularly with C34, a toll-like receptor 4 (TLR4) antagonist. When given before the first pH 4.0 injection, C34 attenuated the muscle and tactile hyperalgesia produced by the model. However, when given before the second injection C34 had no effect on the development of hyperalgesia. Then to test whether activation of local macrophages sensitizes nociceptors to normally non-nociceptive stimuli we replaced either the first or second acid injection with the immune cell activator lipopolysaccharide, or the inflammatory cytokine interleukin (IL)-6. Injecting LPS or IL-6 instead of the either the first or second pH 4.0 injection resulted in a dose-dependent increase in paw withdrawal responses and decrease in muscle withdrawal thresholds. The highest doses of LPS and IL-6 resulted in development of hyperalgesia bilaterally. The present study showed that resident macrophages in muscle are key to development of chronic muscle pain. ⋯ This article presents evidence for the role of macrophages in the development of chronic muscle pain using a mouse model. These data suggest that macrophages could be a potential therapeutic target to prevent transition of acute to chronic muscle pain particularly in tissue acidosis conditions.
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Musculoskeletal pain is associated with multiple adaptions in movement control. This study aimed to determine whether changes in movement control acquired during acute pain are maintained over days of pain exposure. On day 0, the extensor carpi radialis brevis muscle of healthy participants was injected with nerve growth factor (NGF) to induce persistent movement-evoked pain (n = 13) or isotonic saline as a control (n = 13). On day 2, short-lasting pain was induced by injection of hypertonic saline into extensor carpi radialis brevis muscles of all participants. Three-dimensional force components were recorded during submaximal isometric wrist extensions on day 0, day 4, and before, during, and after saline-induced pain on day 2. Standard deviation (variation of task-related force) and total excursion of center of pressure (variation of force direction) were assessed. Maximal movement-evoked pain was 3.3 ± .4 (0-10 numeric scale) in the NGF-group on day 2 whereas maximum saline-induced pain was 6.8 ± .3 cm (10-cm visual analog scale). The difference in centroid position of force direction relative to day 0 was greater in the NGF group than in the control group (P < .05) on day 2 (before saline-induced pain) and day 4, reflecting changes in tangential force direction used to achieve the task. During saline-induced pain in both groups, tangential and task-related force variation was greater than before and after saline-induced pain (P < .05). ⋯ Persistent movement-evoked pain changes force direction from the pain-free direction. Acute pain leads to increased variation in force direction irrespective of persistent movement-evoked pain preceding the acutely painful event. These differences provide novel insight into the search for and consolidation of new motor strategies in the presence of pain.
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Migraine is prevalent and disabling yet is poorly understood. One way to better understand migraine is to examine its clinical characteristics and potential biomarkers such as gamma-aminobutyric acid (GABA). The primary objective of this study was to explore whether relevant disease characteristics of migraine are associated with brain GABA levels. Twenty adults fulfilling the established diagnostic criteria for migraine and 20 age- and gender-matched controls completed this cross-sectional study. Pain, central sensitization, negative emotional state, and perceived disability were measured using Short-form McGill Pain Questionnaire-2, Central Sensitization Inventory, Depression Anxiety Stress Scales-21, and Headache Impact Test-6, respectively. Secondary analysis of brain GABA levels of the same cohort measured using proton magnetic resonance spectroscopy was conducted. The migraine group had significantly higher scores than the control group on pain, central sensitization, and disability. Correlation analyses showed fair positive association between GABA levels and pain and central sensitization scores. No association was found between GABA levels and emotional state and disability. These findings are preliminary evidence supporting the use of questionnaires and GABA levels in characterizing migraine better and broadening the diagnostic process. These findings also strengthen the rationale for the role of GABA in migraine pathophysiology and corroborate the potential of GABA as a migraine biomarker. ⋯ Higher pain and central sensitization scores were associated with increased brain GABA levels in individuals with migraine. These findings offer preliminary evidence for the usefulness of measuring pain and central sensitization in migraine and provide some support for the possible role of GABA in migraine pathophysiology and its potential as a diagnostic marker.
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A classical conditioning framework is often used for clinical reasoning about pain that persists after tissue healing. However, experimental studies demonstrating classically conditioned pain in humans are lacking. The current study tested whether non-nociceptive somatosensory stimuli can come to modulate pain thresholds after being paired with painful nociceptive stimuli in healthy humans. We used a differential simultaneous conditioning paradigm in which one nonpainful vibrotactile conditioned stimulus (CS(+)) was simultaneously paired with an unconditioned painful laser stimulus, and another vibrotactile stimulus (CS(-)) was paired with a nonpainful laser stimulus. After acquisition, at-pain-threshold laser stimuli were delivered simultaneously with a CS(+) or CS(-) vibrotactile stimulus. The primary outcome was the percentage of at-threshold laser stimuli that were reported as painful. The results were as expected: after conditioning, at-threshold laser trials paired with the CS(+) were reported as painful more often, as more intense, and as more unpleasant than those paired with the CS(-). This study provides new evidence that pain thresholds can be modulated via classical conditioning, even when the stimulus used to test the threshold cannot be anticipated. As such, it lays a critical foundation for further investigations of classical conditioning as a possible driver of persistent pain. ⋯ This study provides new evidence that human pain thresholds can be influenced by non-nociceptive somatosensory stimuli, via a classical conditioning effect. As such, it lays a critical foundation for further investigations of classical conditioning as a possible driver of persistent pain.