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 is a pivotal diagnostic indicator, often revealing underlying health issues that require medical care (Lee & Neumeister, 2020).

Pain originates with the activation of nociceptors, which are specialized pain-sensing neurons. Nociceptor cell bodies are established in the sensory ganglia of the peripheral nervous system (PNS), including the dorsal root ganglia (DRG) and the trigeminal ganglia (TG). Sensory neurons project to the spinal cord and the brainstem. Subsequently, second-order neurons transmit signals from these regions to the thalamus and other brain areas, playing a crucial role in pain perception and emotional experience (Gore, 2022).

Pain can be classified according to different attributes, including its origin. Nociceptive pain is caused by tissue damage due to physical (trauma or surgery) and/or chemical agents (Anand & Rajagopal, 2023). Nociplastic pain, introduced in 2016 as a new concept, is characterized as pain resulting from altered nociception, without evidence of tissue damage that would activate peripheral nociceptors or evidence of lesions in the somatosensory system (Kosek et al., 2016). Finally, neuropathic pain occurs following damage or disease affecting the somatosensory system (Petroianu, Aloum & Adem, 2023). This type of pain is described as burning, tingling, or stabbing and may persist despite the absence of visible tissue damage (Finnerup, Kuner & Jensen, 2021). Numerous conditions leading to neuropathic pain include metabolic disorders (e.g., peripheral diabetic neuropathy), viral infections (e.g., post-herpetic neuralgia), autoimmune disorders (including multiple sclerosis and Guillain-Barré syndrome), and chemotherapy-induced and hereditary neuropathies (Petroianu et al., 2023).

Pain epidemiology provides information about its worldwide prevalence, variations across different demographics, and implications for public health (Zimmer, Fraser, Grol-Prokopczyk & Zajacova, 2022). Determining the global prevalence of neuropathic pain is challenging because there is no universally accepted definition of this condition (Baskozos et al., 2023). Nonetheless, prevalence rates have been reported as 8 % in Europe (Liedgens, Obradovic, De Courcy, Holbrook & Jakubanis, 2016), 15.7 % in the United States of America (DiBonaventura et al., 2017), and 17 % in Canada (VanDenKerkhof et al., 2016). As a primary contributor to global disability, it underscores the urgent need for effective pain management strategies and policies to improve healthcare systems (Mills, Nicolson & Smith 2019).

Effective pain management requires a comprehensive understanding of its underlying causes. Clinicians must possess the expertise and resources to accurately assess pain, considering various factors such as its severity, duration, and impact on daily activities (Karcioglu, Topacoglu, Dikme & Dikme, 2018). A patient-centered approach is essential in pain control, ensuring that treatment strategies are customized to the individual circumstances (Kim & Dionne, 2009). This requires implementing a multidisciplinary approach, incorporating pharmacological and psychological therapies (Kim & Dionne, 2009).

Many investigations have accentuated the importance of proinflammatory cytokines in initiating and progressing neuropathic pain (Hung, Lim & Doshi, 2017). Cytokines are soluble proteins secreted by various immune cells, including lymphocytes, macrophages, natural killer (NK) cells, mast cells, and stromal cells (Kany, Vollrath & Relja, 2019). These proteins participate in the immune response and serve as critical mediators within the communication network of the immune system (Kany et al., 2019).

A substantial body of research has consistently demonstrated a robust correlation between elevated levels of proinflammatory cytokines and the severity of pain experienced by patients with neuropathic pain conditions. Excessive release of proinflammatory cytokines, such as TNF-α, resulting from infection or nerve injury can induce pain (Hess et al., 2011). TNF-α is an essential regulator of inflammatory responses, given its significant role in the development of varied inflammatory and autoimmune diseases (Jang et al., 2021). Structurally, TNF-α is a homotrimeric protein with 157 αα, synthesized by activated macrophages, T lymphocytes, and NK cells (Kalliolias & Ivashkiv, 2016). It is well established that TNF-α stimulates the release of many inflammatory mediators, such as other cytokines (Terrando et al., 2010). This cytokine is involved in pain modulation due to numerous reasons: (i) sensitization of nociceptors (TNF-α contributes to the peripheral sensitization; Durham, Hawkins & Durham, 2017); (ii) activation of pain pathways (TNF-α strongly stimulates the ascending pain pathway through its role in central sensitization; Andrade et al., 2011); (iii) interaction with other pain modulators (TNF-α can enhance the expression of another pain-related mediators; Biesmans et al., 2015).

Additionally, the immune system has attracted increasing attention for its crucial role in the resolution of pain through its interactions with the nervous system (Daëron, 2022). Therefore, it is essential to enhance the immune system to mitigate the unpleasant effects of pain. To achieve this, immunotherapy treatments with monoclonal antibodies are effective in treating various pathologies associated with severe pain, such as rheumatoid arthritis (Tuttle et al., 2023), migraine (Cohen et al., 2021), osteoarthritis (LaBranche et al., 2017), chronic low back pain (Gjefsen et al., 2020), or diabetic neuropathy (Bramson et al., 2015).

This chapter will discuss the most relevant aspects of the TNF-α cytokine. It will start with a detailed examination of its biology, followed by an analysis of its role in the initiation and development of neuropathic pain. Finally, a comprehensive evaluation will be conducted to assess the effectiveness of anti-TNF-α antibodies in treating neuropathic pain.