Pain and inflammation are both protective responses in living organisms. However, these self-limiting conditions (with established negative feedback loops) become pathological if left unchecked. This review briefly explains nociception and inflammation. This is followed by a detailed description of the role of immune and related cells in peripheral sensitization, the phenomenon of neurogenic inflammation, and alterations of the sensory ganglia and central nervous system due to the immune system during nociception. Innate immunity plays a critical role in central sensitization and in establishing acute pain as a chronic condition. Furthermore, inflammatory mediators also exhibit psychological effects, thus contributing to the emotional elements associated with pain. However, there is a considerable role of the immune system as an analgesic and in pain relief. This review also attempts to list various new pharmacological approaches that show their action through modification of the neuro-immune interface. Introduction One of the most vital functions of the nervous system is to provide information about the onset or threat of injury. On the other hand, inflammation is a protective response involving host cells, blood vessels, proteins and other mediators, which is aimed at eliminating the initial cause of cell damage, as well as necrotic cells and tissues resulting from the insult original, and to start the repair process. A long-standing interest of pain scientists has been the identification of chemical mediators released in injured or diseased tissues that are responsible for the associated abnormal pain states. Additionally, it is well known that the immune system can alter sensory processing and play a critical role in the development… half of the article… prolonged acute pain. A disproportion of pro-inflammatory and anti-inflammatory drugs, inflammatory cytokines are known to contribute to pain and pain behavior. Embedded in psychoneuroendocrine and immunological feedback control systems, cytokines are capable of perpetuating a vicious connection between local inflammation and systemic pain behavior (pain/illness behavior), contributing to the chronicity of nonspecific musculoskeletal pain. TNF-α (via NF-κB in astrocytes) causes the release of CCL-2, which interacts positively with NMDA and AMPA receptors in neurons. This negatively affects the modulation of central descending pain leading to failure of the resolution state. Furthermore; The co-localization of IL-1β and NMDA receptors on the neuron and the phosphorylation of NMDA after being stimulated by IL-1 explains the direct role of the immune system in establishing the nociceptive neuronal circuit.