The International Association for the Study of Pain (IASP) has defined pain as “an unpleasant sensory and emotional experience associated with or resembling that associated with actual or potential tissue damage” (Raja et al., 2020). Pain functions as a critical diagnostic marker, often indicating underlying health conditions that require medical care (Lee & Neumeister, 2020). This sensation begins with the activation of specialized pain-sensing neurons, known as nociceptors. Nociceptor cell bodies are located within the sensory ganglia of the peripheral nervous system (PNS), including the dorsal root ganglia (DRG) and trigeminal ganglia (TG). These sensory neurons project to the spinal cord and brainstem. Subsequently, second-order neurons transmit signals from these regions to the thalamus and other brain areas, playing a pivotal role in pain perception and the emotional experience of pain (Gore, 2022). However, this process can be disrupted, resulting in chronic pain conditions that complicate the development of effective pain relief therapies. While nociceptive pathways are well-understood, additional research is essential to unravel the complexities of pain modulation, as significant gaps in knowledge persist (Cao et al., 2024).

Pain can be classified based on various attributes, including its origin. Neuropathic pain arises from injury or disease that affects the somatosensory system (Petroianu, Aloum, & Adem, 2023). Nociplastic pain is characterized by pain resulting from altered nociception, without evidence of tissue damage that would activate peripheral nociceptors or cause lesions in the somatosensory system (Kosek et al., 2016). Finally, nociceptive pain is generated from tissue damage caused by physical factors (such as trauma or surgery) and/or chemical agents (Anand & Rajagopal, 2023).

Inflammatory pain is a subclass of nociceptive pain that represents a physiological response to tissue damage or injury, characterized by increased sensitivity to stimuli within the affected region (Su, Sun, & Chen, 2014). This type of pain is mediated by a cascade of several molecular and cellular events that occur in the peripheral (PNS) and central (CNS) nervous systems. In the periphery, tissue damage triggers the release of an inflammatory soup composed of numerous mediators, encompassing prostaglandins, bradykinins, serotonin, histamine, cytokines, H+, and adenosine triphosphate (ATP) (Fig. 1). These mediators sensitize nociceptors through several mechanisms, such as the activation of TRPV1 channels (transient receptor potential vanilloid 1; Schumacher, 2010) and ASICs (acid-sensing ion channels; Abdelhamid & Sluka, 2015), and the modulation of GPCRs (G protein-coupled receptors; Sun & Ye, 2012). This event culminates in peripheral sensitization, in which nociceptors display hyperexcitability, leading them to respond more intensively to stimuli (Lopes et al., 2017). Simultaneously, immune cells (e.g., macrophages and neutrophils) infiltrate the injured area, releasing several proinflammatory cytokines, which further amplify the inflammatory response and contribute to the maintenance of pain (Kidd & Urban, 2001). At the CNS level, chronic nociceptor activation leads to central sensitization. This process involves the release of numerous neurotransmitters and other neuromodulators (such as glutamate, substance P, and calcitonin gene-related peptide – CGRP) that enhance synaptic efficacy (Ji et al., 2018). The activation of the N-methyl-D-aspartate receptor (NMDAR) increases Ca2+ influx, triggering signaling cascades that sustain central sensitization (Weyerbacher et al., 2010). Additionally, glial cells become activated and release proinflammatory mediators, which further support the persistence of inflammatory pain (Wang & Xu, 2022).

Over time, persistent inflammatory pain can cause long-term changes in gene expression and neuroplasticity, potentially progressing into chronic pain states that share many similarities with neuropathic pain conditions (Xu & Yaksh, 2011). This complex interplay between peripheral and central mechanisms leads to hyperalgesia (increased pain sensitivity) and allodynia (pain elicited by stimuli that are usually non-painful), which are hallmarks of inflammatory pain conditions (Sandkühler, 2009). Some studies have highlighted the critical role of proinflammatory cytokines in the onset and progression of inflammatory pain (Cook et al., 2018). Cytokines are soluble proteins secreted by immune cells, including lymphocytes, macrophages, NK (natural killer) cells, mast cells, and stromal cells. These proteins play a pivotal role in the immune response and act as key mediators within the immune system’s communication network (Kany, Vollrath, & Relja, 2019). A significant body of research has shown a strong association between increased levels of proinflammatory cytokines and the intensity of inflammatory pain.

In the context of inflammatory pain, there is an excessive release of several proinflammatory cytokines, particularly interleukin 23 (IL-23). IL-23 is critical for the immune system’s response to pathogens and contributes to the development of numerous inflammatory diseases. Composed of two subunits, p19 (IL-23p19) and p40 (IL-23p40), IL-23 is predominantly produced by activated dendritic cells and macrophages (Krueger et al., 2024). This cytokine plays a crucial role in the differentiation and maintenance of Th17 cells, which are involved in the inflammatory response (Bunte & Beikler, 2019). IL-23 exerts its biological effects by binding to the IL-23 receptor (IL-23R), triggering a signaling cascade that leads to the production of other proinflammatory cytokines, including interleukin 17 (IL-17), interleukin 22 (IL-22), TNF-α (tumor necrosis factor alpha), and GM-CSF (granulocyte-macrophage colony-stimulating factor) (Pastor-Fernández et al., 2020, Łukasik et al., 2021). IL-23 is involved in pain modulation for three reasons: (i) interaction with nociceptors (IL-23 amplifies pain induced by the activation of nociceptors; Ji et al., 2021); (ii) macrophage-neuron crosstalk (IL-23 prompts macrophages to release IL-17, which activates the IL-17 receptor -IL-17R- located on nociceptors, thereby eliciting inflammatory pain; Luo et al., 2021); (iii) interaction with other cytokines (pain induced by IL-23 is mediated through TNF-α, GM-CSF, and C-C chemokine ligand 17 -CCL17- action; Lee et al., 2020). These findings highlight the complexity of pain mechanisms, particularly considering the involvement of multiple pathways. The interaction between various mediators suggests that our understanding of nociceptive signaling must continue to evolve.

Additionally, the immune system has received increasing attention for its essential role in pain resolution through interactions with the nervous system (Daëron, 2022). Consequently, boosting the immune system is crucial for reducing the severity of pain associated with inflammatory diseases. To achieve this goal, immunotherapy treatments with monoclonal antibodies are highly effective in numerous diseases accompanied by intense pain, such as rheumatoid arthritis (Tuttle et al., 2023), psoriatic arthritis (Singla et al., 2023), inflammatory bowel disease (Catalan-Serra & Brenna, 2018), and systemic lupus erythematosus (Zavaleta-Monestel et al., 2024).

This chapter will explore the most relevant aspects of the IL-23 cytokine. It will begin with a detailed analysis of its biology, followed by a discussion of its role in the onset and progression of inflammatory pain. Finally, a comprehensive evaluation will be presented to assess the efficacy of anti-IL-23 antibodies in the treatment of pain-related inflammatory diseases.