PD-1/PD-L1 Inhibition Enhances Chemotherapy-Induced Neuropathic Pain by Suppressing Neuroimmune Antinociceptive Signaling.

Cytotoxic agents synergize with immune checkpoint inhibitors and improve outcomes for patients with several cancer types. Nonetheless, a parallel increase in the incidence of dose-limiting side effects, such as peripheral neuropathy, is often observed. Here, we investigated the role of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis in the modulation of paclitaxel-induced neuropathic pain. We found that human and mouse neural tissues, including the dorsal root ganglion (DRG), expressed basal levels of PD-1 and PD-L1. During the development of paclitaxel-induced neuropathy, an increase in PD-L1 expression was observed in macrophages from the DRG. This effect depended on Toll-like receptor 4 activation by paclitaxel. Furthermore, PD-L1 inhibited pain behavior triggered by paclitaxel or formalin in mice, suggesting that PD-1/PD-L1 signaling attenuates peripheral neuropathy development. Consistent with this, we observed that the combined use of anti-PD-L1 plus paclitaxel increased mechanical allodynia and chronic neuropathy development induced by single agents. This effect was associated with higher expression of inflammatory markers (Tnf, Il6, and Cx3cr1) in peripheral nervous tissue. Together, these results suggest that PD-1/PD-L1 inhibitors enhance paclitaxel-induced neuropathic pain by suppressing PD-1/PD-L1 antinociceptive signaling.

Low-Intensity Photobiomodulation Decreases Neuropathic Pain in Paw Ischemia-Reperfusion and Spared Nervus Ischiadicus Injury Experimental Models.

BACKGROUND: There is a wide range of animal models available today for studying chronic pain associated with a variety of etiologies and an extensive list of clinical manifestations of peripheral neuropathies. Photobiomodulation is a new tool for the treatment of pain in a convenient, noninvasive way. OBJECTIVE: The aim of this work is to elucidate the effects of infrared light-emitting diodes (LEDs) on behavioral responses to nociceptive stimuli in chronic pain models. METHODS: Forty-eight Swiss male mice weighing 25 to 35 g were used. Two chronic pain models, ischemia-reperfusion (IR) and spared spinal nerve injury, were performed and then treated with infrared LED irradiation (390 mW, 890 nm, 17.3 mW/cm2 , 20.8 J/cm2 , for 20 minutes). The behavioral tests used were a mechanical hypersensitivity test von Frey test) and a cold allodynia test (acetone test). RESULTS: The results showed that, in the IR model, the infrared LED had a significant effect on mechanical stimulation and cold allodynia on every day of treatment. In the spared nerve injury model, an analgesic effect was observed on every treatment day (when started on the 3rd and 7th days after the surgery). In both models, the effect was abolished when the treatment was interrupted. CONCLUSIONS: These findings suggest that photobiomodulation therapy may be a useful adjunct treatment for chronic pain.