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The endogenous metabolite methylglyoxal (MG) accumulates in diabetic patients with neuropathic pain. Methylglyoxal could be a mediator of diabetes-induced neuropathic pain through TRPA1 activation and sensitization of the voltage-gated sodium channel subtype 1.8. In this study, we tested the algogenic and sensitizing effect of MG in healthy human subjects using intracutaneous microinjections. The involvement of C fibers was assessed through selective A-fiber nerve block, axon-reflex-erythema, and through single nerve fiber recordings in humans (microneurography). Involvement of the transduction channels TRPA1 and TRPV1 in MG-induced pain sensation was investigated with specific ion channel blockers. We showed for the first time in healthy humans that MG induces pain, axon-reflex-erythema, and long-lasting hyperalgesia through the activation of C nociceptors. Predominantly, the subclass of mechano-insensitive C fibers is activated by MG. A fibers contribute only negligibly to the burning pain sensation. Selective pharmacological blockade of TRPA1 or TRPV1 showed that TRPA1 is crucially involved in MG-induced chemical pain sensation and heat hyperalgesia. In conclusion, the actions of MG through TRPA1 activation on predominantly mechano-insensitive C fibers might be involved in spontaneously perceived pain in diabetic neuropathy and hyperalgesia as well as allodynia.

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Purpose of Review Chronic pruritus represents a burdensome symptom in cholestatic liver disease. This review recommends a stepwise therapeutic approach, alongside with providing information on epidemiology, pathophysiology, and novel drug targets. Recent Findings Current epidemiological data emphasize chronic itch as a major symptom in immune-mediated liver diseases such as primary biliary cholangitis affecting up to 70% of patients with a significant number suffering from long-lasting and severe pruritus. κ-opioid receptor (KOR) agonists, PPAR agonists, and ileal bile acid transporter (IBAT) inhibitors are currently investigated for their anti-pruritic efficacy in clinical trials. Future therapies may target the autotaxin-lysophosphatidic acid-axis or the Mas-related GPCR MRGPRX4. Summary Cholestatic pruritus still remains a challenging symptom for patients and physicians. Using a stepwise approach including cholestyramine, rifampicin, bezafibrate, naltrexone, and sertraline, pruritus is often adequately manageable. KOR agonists and IBAT inhibitors are currently the most promising anti-pruritic drugs for cholestatic pruritus in development.

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