The analgesic effect of programmed cell death protein-1.

mental research paper about the heparanase and cancer pain progression was presented [1]. Heparanase treatment aggravated mechanical allodynia, cold response, and spontaneous pain. Additionally, the contents of inflammatory cytokines (TNF-α, NF-κB, IL-1β, and IL-6) was increased, and programmed death-ligand 1 (PD-L1) level was decreased in tumor tissue. Inversely, the heparanase inhibitor (SST0001) exhibited opposite results [1]. Programmed cell death protein 1, also known as PD-1, is a type I transmembrane glycoprotein and a cell surface receptor. PD-1 is broadly presented on cytotoxic T cells, regulatory T cells, B cells, natural killer cells, microglia, macrophages, and certain types of neurons [2–4]. PD-1 has a role in suppressing the inflammatory actions of T cells. Therefore, the immune system is downregulated, self-tolerance is promoted, autoimmune diseases are attenuated, and killing actions against cancer cells by the immune system could be prevented [5]. PD-1 is an essential and negatively acting regulator related to diverse biological effects and diseases, such as cancer immunotherapy, brain tumors, Alzheimer’s disease, stroke, multiple sclerosis and cognitive dysfunctions [6,7]. PD-1 signaling modulates synaptic plasticity, synaptic transmission, and neuronal excitability in neurons [2]. The neuronal signaling of PD-1 regulates pain by modulating dephosphorylating transient receptor potential subtype V1 (TRPV1) [8], GABAergic neurotransmission [4], and sodium/potassium channels [3]. In an experiment with Pd1 knockout mice, Pd1 knockout mice were more sensitive to pain stimulation than wild type mice, and it presented that PD-1 performs a crucial role in the modulation of pain [3]. Additionally, the activation of PD-1 signaling by PD-L1 is related to the regulations of μ-opioid receptor signals in the nociceptive neurons, and it enhances the antinociceptive actions of morphine [9]. Therefore, small molecular peptides targeting PD-1 could be an alternative medicine for treating chronic pain. On the other hand, PD-1 inhibitors, a newly developed class of anticancer medicine that block PD-1, could activate the immune system to attack cancer cells and could be used to treat special types of cancers [5]. For example, Pembrolizumab is a humanized IgG4 isotype antibody, and it blocks a protective mechanism of cancer cells and allows the immune system to destroy cancer cells. It targets the PD-1 receptor of lymphocytes and acts by targeting the cellular pathway of proteins, known as PD-1/PDL1, found on the immune cells and certain cancer cells. Pembrolizumab is used as an immunotherapy medicine