Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0344307 (analgesia)
 28,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Programmed cell death ligand-1 (PD-L1) is typically produced by cancer cells and suppresses immunity through the receptor PD-1 expressed on T cells. However, the role of PD-L1 and PD-1 in regulating pain and neuronal function is unclear. Here we report that both melanoma and normal neural tissues including dorsal root ganglion (DRG) produce PD-L1 that can potently inhibit acute and chronic pain. Intraplantar injection of PD-L1 evoked analgesia in naive mice via PD-1, whereas PD-L1 neutralization or PD-1 blockade induced mechanical allodynia. Mice lacking Pd1 (Pdcd1) exhibited thermal and mechanical hypersensitivity. PD-1 activation in DRG nociceptive neurons by PD-L1 induced phosphorylation of the tyrosine phosphatase SHP-1, inhibited sodium channels and caused hyperpolarization through activation of TREK2 K+ channels. PD-L1 also potently suppressed nociceptive neuron excitability in human DRGs. Notably, blocking PD-L1 or PD-1 elicited spontaneous pain and allodynia in melanoma-bearing mice. Our findings identify a previously unrecognized role of PD-L1 as an endogenous pain inhibitor and a neuromodulator.
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PMID:PD-L1 inhibits acute and chronic pain by suppressing nociceptive neuron activity via PD-1. 3064

Immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 antibodies) are a standard of care for advanced melanoma. Novel toxicities comprise immune-related adverse events (irAE). With increasing use, irAE require recognition, practical management strategies, and multidisciplinary care. We retrospectively evaluated the incidence, kinetics, and management of irAE in 41 patients receiving anti-PD-1 antibody therapy (pembrolizumab) for advanced melanoma. 63% received prior anti-CTLA-4 antibody therapy (ipilimumab). IrAE occurred in 54%, most commonly dermatological (24%), rheumatological (22%), and thyroid dysfunction (12%). Thyroiditis was characterised by a brief asymptomatic hyperthyroid phase followed by a symptomatic hypothyroid phase requiring thyroxine replacement. Transplant rejection doses of methylprednisolone were necessary to manage refractory hepatotoxicity. A bullous pemphigoid-like skin reaction with refractory pruritus responded to corticosteroids and neuropathic analgesia. Disabling grade 3-4 oligoarthritis required sulfasalazine therapy in combination with steroids. The median interval between the last dose of anti-CTLA-4 antibody and the first dose of anti-PD-1 therapy was 2.0 months (range: 0.4 to 22.4). Toxicities may occur late; this requires vigilance and multidisciplinary management which may allow effective anticancer therapy to continue. Management algorithms for thyroiditis, hypophysitis, arthralgia/arthritis, colitis, steroid-refractory hepatitis, and skin toxicity are discussed.
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PMID:Immune Toxicity with Checkpoint Inhibition for Metastatic Melanoma: Case Series and Clinical Management. 2961 Jun 84

Recently programmed death-ligand 1 (PD-L1) receptor PD-1 was found in dorsal root ganglion (DRG) neurons, and PD-L1 activates PD-1 to inhibit inflammatory and neuropathic pain by modulating neuronal excitability. However, the downstream signaling of PD-1 in sensory neurons remains unclear. Here, we show that PD-L1 activated Src homology 2 domain-containing tyrosine phosphatase-1 (SHP-1) to downregulate transient receptor potential vanilloid 1 (TRPV1) in DRG neurons and inhibit bone cancer pain in mice. Local injection of PD-L1 produced analgesia. PD-1 in DRG neurons colocalized with TRPV1 and SHP-1. PD-L1 induced the phosphorylation of SHP-1 in DRG TRPV1 neurons and inhibited TRPV1 currents. Loss of TRPV1 in mice abolished bone cancer-induced thermal hyperalgesia and PD-L1 analgesia. Conditioned deletion of SHP-1 in NaV1.8+ neurons aggravated bone cancer pain and diminished the inhibition of PD-L1 on TRPV1 currents and pain. Together, our findings suggest that PD-L1/PD-1 signaling suppresses bone cancer pain via inhibition of TRPV1 activity. Our results also suggest that SHP-1 in sensory neurons is an endogenous pain inhibitor and delays the development of bone cancer pain via suppressing TRPV1 function.
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PMID:Inhibition of TRPV1 by SHP-1 in nociceptive primary sensory neurons is critical in PD-L1 analgesia. 3296 Aug 17