Articles: hyperalgesia.
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Central sensitization (CS) is believed to play a role in many chronic pain conditions. Direct non-invasive recording from single nociceptive neurons is not feasible in humans, complicating CS establishment. This review discusses how secondary hyperalgesia (SHA), considered a manifestation of CS, affects physiological measures in healthy individuals and if these measures could indicate CS. It addresses controversies about heat sensitivity changes, the role of tactile afferents in mechanical hypersensitivity and detecting SHA through electrical stimuli. Additionally, it reviews the potential of neurophysiological measures to indicate CS presence. ⋯ Gathering evidence for CS in humans is a crucial research focus, especially with the increasing interest in concepts such as 'central sensitization-like pain' or 'nociplastic pain'. This review clarifies which readouts, among the different behavioural and neurophysiological proxies tested in experimental settings, can be used to infer the presence of CS in humans.
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This experiment aimed at confirming our incidental observation that, when capsaicin is applied on the volar forearm, raising the arm to a vertical position leads to a dramatic increase in capsaicin-evoked pain and to explore possible underlying mechanisms. ⋯ Capsaicin-evoked pain can be strongly modulated by limb posture and this effect may be caused by an interplay between vascular and nociceptive systems.
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High molecular weight hyaluronan (HMWH) inhibits hyperalgesia induced by diverse pronociceptive inflammatory mediators and their second messengers, in rats of both sexes. However, the hyperalgesia induced by ligands at 3 pattern recognition receptors, lipopolysaccharide (a toll-like receptor 4 agonist), lipoteichoic acid (a toll-like receptor 2/6 agonist), and nigericin (a NOD-like receptor family, pyrin domain containing 3 activator), and oxaliplatin and paclitaxel chemotherapy-induced peripheral neuropathy are only attenuated in males. After gonadectomy or intrathecal administration of an antisense to G-protein-coupled estrogen receptor 30 (GPER) mRNA, HMWH produces antihyperalgesia in females. ⋯ In females, hyperalgesia induced by PKCε agonist, ψεRACK, in control but not in primed nociceptors, was inhibited by HMWH. Inhibitors of 2 GPER second messengers, extracellular-regulated kinase 1/2 and nonreceptor tyrosine kinase, also unmasked HMWH antihyperalgesia in females with oxaliplatin chemotherapy-induced peripheral neuropathy, a condition in which nociceptors are primed as well as sensitized. Our results support GPER-dependent sex dimorphism in HMWH-induced antihyperalgesia for pain induced by pattern recognition receptor agonists, and chronic inflammatory and neuropathic pain, mediated by changes in signaling downstream of PKCε in primed nociceptors.
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Repetitive ischemia with reperfusion (I/R) injury is a common cause of myalgia. Ischemia with reperfusion injuries occur in many conditions that differentially affect males and females including complex regional pain syndrome and fibromyalgia. Our preclinical studies have indicated that primary afferent sensitization and behavioral hypersensitivity caused by I/R injury may be due to sex-specific gene expression in the dorsal root ganglia (DRG) and distinct upregulation of growth factors and cytokines in the affected muscles. ⋯ AUF1 knockdown was able to specifically inhibit repeated I/R-induced gene expression in females potentially downstream of prolactin receptor signaling. Data suggest RNA-binding proteins such as pAUF1 may underlie the sex-specific effects on DRG gene expression that modulates behavioral hypersensitivity after repeated I/R injury through prolactin signaling. This study may aid in finding distinct receptor differences related to the evolution of acute to chronic ischemic muscle pain development between sexes.
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Treating bone cancer pain (BCP) continues to be a clinical challenge, and the underlying mechanisms of BCP remain elusive. This study reports that Wnt5a/Ryk signaling in the dorsal root ganglion neurons is critical to the development of BCP. Tibia bone cavity tumor cell implantation produces spontaneous and evoked behaviorally expressed pain as well as ectopic sprouting and activity of Wnt5a/Ryk signaling in the neural soma and peripheral terminals and the tumor-affected bone tissues. ⋯ Blocking Ryk receptor activation suppresses Wnt5a-induced mechanical allodynia and thermal hyperalgesia. Wnt5a facilitation of transient receptors potential vanilloid type-1 sensitization is blocked by inhibiting c-Jun N-terminal kinase activation. These findings indicate a critical peripheral mechanism of Wnt5a/Ryk signaling underlying the pathogenesis of BCP and suggest that targeting Wnt5a/Ryk in the primary sensory neurons and the tumor-invasive area may be an effective approach for the prevention and treatment of BCP.