Mechanisms and treatments of neuropathic itch in a mouse model of lymphoma
Ouyang Chen, … , Madelynne Olexa, Ru-Rong Ji
Ouyang Chen, … , Madelynne Olexa, Ru-Rong Ji
Published December 15, 2022
Citation Information: J Clin Invest. 2023;133(4):e160807. https://doi.org/10.1172/JCI160807.
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Research Article Neuroscience

Mechanisms and treatments of neuropathic itch in a mouse model of lymphoma

Abstract

Our understanding of neuropathic itch is limited due to a lack of relevant animal models. Patients with cutaneous T cell lymphoma (CTCL) experience severe itching. Here, we characterize a mouse model of chronic itch with remarkable lymphoma growth, immune cell accumulation, and persistent pruritus. Intradermal CTCL inoculation produced time-dependent changes in nerve innervations in lymphoma-bearing skin. In the early phase (20 days), CTCL caused hyperinnervations in the epidermis. However, chronic itch was associated with loss of epidermal nerve fibers in the late phases (40 and 60 days). CTCL was also characterized by marked nerve innervations in mouse lymphoma. Blockade of C-fibers reduced pruritus at early and late phases, whereas blockade of A-fibers only suppressed late-phase itch. Intrathecal (i.t.) gabapentin injection reduced late-phase, but not early-phase, pruritus. IL-31 was upregulated in mouse lymphoma, whereas its receptor Il31ra was persistently upregulated in Trpv1-expressing sensory neurons in mice with CTCL. Intratumoral anti–IL-31 treatment effectively suppressed CTCL-induced scratching and alloknesis (mechanical itch). Finally, i.t. administration of a TLR4 antagonist attenuated pruritus in early and late phases and in both sexes. Collectively, we have established a mouse model of neuropathic and cancer itch with relevance to human disease. Our findings also suggest distinct mechanisms underlying acute, chronic, and neuropathic itch.

Authors

Ouyang Chen, Qianru He, Qingjian Han, Kenta Furutani, Yun Gu, Madelynne Olexa, Ru-Rong Ji

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Figure 10

Excitatory synaptic transmission in spinal cord slices from naive and CTCL mice.

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Excitatory synaptic transmission in spinal cord slices from naive and CT...
(A and B) Representative traces of sEPSCs from spinal dorsal horn neurons from naive CB17 and early-phase CTCL mice. (C and D) CTCL was associated with significant increase in sEPSC frequency (C) but not sEPSC amplitude (D). Unpaired, 2-tailed Student’s t test, n = 12 neurons (naive) and n = 15 neurons (CTCL). (E–I) Inhibition of sEPSCs by perfusion of spinal cord slices with NPD1 (30 ng/mL) in CTCL day-20 mice. (E) Representative traces of sEPSCs before and during the perfusion of NPD1 (30 ng/mL). Bottom: Enlarged sEPSC traces on a short time scale. (F and G) NPD1 significantly reduced sEPSC frequency without affecting sEPSC amplitude. Significance was determined by paired, 2-tailed Student’s t test. n = 10 neurons/group. (H and I) Cumulative histograms of the inter-event intervals and amplitudes of sEPSCs before and after NPD1 perfusion. The histograms were examined for 1 minute before and during NPD1 treatment. The inter-event interval was significantly prolonged and the amplitude was significantly decreased by NPD1. Significance was determined by Kolmogorov-Smirnov 2-sample test. Data indicate the mean ± SEM. n = 3–4 animals/group.