Editorial: Chronic pain: what is the mechanism?

Long et al (URL=h ps://www.fron ersin.org/journals/pharmacology/ar cles/10.3389/fphar.2022.910885) in this issue have published their work on bufalin-PLGA as a treatment for neuropathic pain. Bufalin is derived from toad venom and was found to decrease the levels of IL-1β, IL-18 and TNFα during chronic pain. The expression of transient receptor poten al ca on channels of the vanilloid 1 type (TRPV1) and purinergic 2X7 receptors increased during chronic pain and decreased a er bufalin administra on. These receptors are important in pain and chronic pain. IL-1β and IL-18 increase the synthesis and release of several chemokines (5,6). TNFα also s mulates the synthesis and release of chemokines (7). By decreasing chemokine produc on, bufalin may alleviate chronic pain. Chemokines have been implicated in a pain chemokine cycle that may be involved in chronic pain (3,4).Shen et al (URL=h ps://www.fron ersin.org/journals/pharmacology/ar cles/10.3389/fphar.2024.1200492) review the mechanisms of inflamma on in re nal diseases. IL 1β, IL-6, IL-10, IL-12 levels increase in these condi ons and may be in causing hyperpermeability of the choroid leading to edema and inflamma on. These cytokines increase the release of chemokines including MCP-1 and IL-8, that a ract inflammatory cells such as macrophages, T cells and B cells into the re na (5,6). Dendri c cells also become ac vated due to the ac ons of these chemokines. Immunotherapy development is ongoing to find ways to decrease the ac ons of these inflammatory chemokines. Kuo et al (URL=h ps://www.fron ersin.org/journals/pharmacology/ar cles/10.3389/fphar.2024.1346801) inves gated a new somatosta n type 4 receptor agonist in pain, chronic pain and inflamma on. Somatosta n agonists are known to act on inflammatory macrophages and decrease the secre on of IL-8 and MCP-1 by these macrophages (8). These chemokines are important in pain and inflamma on (3,4). This may be involved in the allevia on of pain, chronic pain and inflamma on by J-2156.Heinle et al (URL=h ps://www.fron ersin.org/journals/pharmacology/ar cles/10.3389/fphar.2024.1398409) discuss the importance of NaV1.8 channels in chronic pain. NaV1.8 is expressed in several ssues including the brain, brain stem and skin (9). The receptor is important in pain sensa on and complements TRP channels, which are the most abundant pain receptors. Chemokines, such as CCL2 are known to increase NaV1.8 expression in chronic pain (10), just as chemokines increase TRP channel expression in chronic pain (3,4). It is important to remember that visceral neurons have peripheral projec ons into the skin which is where much of the visceral pain is sensed in NaV1.8 receptors and TRP channels (3,4).In this issue, the importance of the pain chemokine cycle is elucidated. Chemokines increase pain by ac va ng and inducing pain receptors and a rac ng inflammatory cells. Macrophages are a racted by chemokines and produce prostaglandins since they express cyclo-oxygenase 2. Prostaglandins interact with prostaglandin receptors to cause pain and transac vate TRP channels to cause more pain and chemokine release (3,4). Neutrophils are a racted by chemokines to sites of pain and inflamma on and secrete that cause long term ac va on of TRP channels and pain (3,4). This pain chemokine cycle is largely located in the skin and can last for many years.