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Background: Multiple factors, including neurobiological, hormonal, psychological, and social/cultural norms, influence the manner in which individuals experience pain. Adipose tissue, once considered solely an energy storage site, has been recognized as a significant endocrine organ that produces and releases a range of hormones and cytokines. In recent years, research has highlighted the role of adipose tissue and its endocrine factors in the pathophysiology of pain. Summary: This narrative review aimed to provide a comprehensive overview of the current knowledge on the endocrine aspects of pain pathophysiology, with a specific focus on adipose tissue. We examine the role of adipokines released by adipose tissue, such as leptin, adiponectin, resistin, visfatin, asprosin in pain perception and response. We also explore the clinical implications of these findings, including the potential for personalized pain management based on endocrine factors and adipose tissue. Key Messages: Overall, given this background, this review intended to highlight the importance of understanding the endocrine aspects of pain pathophysiology, particularly focusing on the role of adipose tissue, in the development of chronic pain and adipokines. Better understanding the role of adipokines in pain modulation might have therapeutic implications by providing novel targets for addressing underlying mechanism rather than directly focusing on symptoms for chronic pain, particularly in obese individuals.

There are strong implications of interactions between adipose tissue and pain sensation. This complex interaction involves endocrine and paracrine actions of adipose tissue release products on pain signaling. Adipose tissue produces and releases various hormones and cytokines, known as adipokines, which can act locally on peripheral sensory nerves and also systemically on distant organs and tissues. These effects include actions of adipokines as neurotransmitter as well as modulatory actions on neurotransmitter release, synaptic plasticity, and immune functions. Adipokines also have paracrine effects within the adipose tissue, regulating adipocyte differentiation, inflammation, and metabolism. Adipokines can act through endocrine or paracrine pathways to modulate pain perception and response, and their effects may vary depending on the type and location of the pain. Dysregulation of adipokine signaling has been linked to the development and maintenance of various chronic pain conditions, including osteoarthritis (OA), fibromyalgia, and chronic low back pain. Therefore, further research is needed to understand the precise mechanisms underlying the adipose tissue-pain interaction and to identify potential targets for therapeutic interventions in chronic pain management. Understanding the role of adipose tissue in pain perception and modulation offers new avenues for targeted therapies and personalized pain management.

Overview of Pain Pathophysiology and the Endocrine System

Pain is a multifaceted experience that involves physiological, psychological, and social factors. The endocrine system, with its extensive network of hormones and receptors, plays a vital role in pain perception and modulation [1‒4]. The hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, as well as adipose tissue, have been implicated in the pathophysiology of pain. The hypothalamic-pituitary-adrenal axis is a fundamental endocrine pathway involved in regulating the stress response [5], and its dysregulation has been linked to various chronic pain conditions [5, 6]. The hypothalamic-pituitary-gonadal axis plays a crucial role in pain perception and modulation, with gender-specific effects on pain perception mediated by estrogen and testosterone levels [7]. Insulin, a hormone crucial for regulating glucose levels in the body, is not only involved in maintaining proper glucose homeostasis but has also been linked to the perception and modulation of pain. Additionally, insulin resistance, a condition where cells become less responsive to insulin, is associated with a heightened risk of experiencing chronic pain [8]. Leptin, an adipose-derived hormone, has also been linked to pain perception and modulation, with leptin resistance associated with chronic pain development [9].

Adipose tissue, traditionally regarded as an energy storage site, is now recognized as an important endocrine organ that produces and releases various hormones and cytokines known as adipokines that have different effects on pain perception and modulation [10]. Inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) are also produced by adipose tissue in addition to macrophages, monocytes, and T cells have been implicated to associate with chronic pain conditions [11]. Understanding the complex interplay between the endocrine system, adipose tissue, and pain perception and pain modulation is critical for the development of more effective pain management strategies. This review aimed to provide an overview of the endocrine aspects of pain pathophysiology, with a specific focus on adipose tissue.

Adipose Tissue as an Active Endocrine Organ

Adipose tissue, traditionally regarded as an energy storage and insulating tissue, has gained recognition as a complex endocrine organ. It produces and releases a diverse range of cytokines, hormones, and growth factors that not only act on neighboring cells but also target tissues involved in energy metabolism, regulating a wide range of physiologic and pathologic processes [12]. However, excessive or inadequate adipose tissue in the body can lead to dysregulation of these functions, resulting in various metabolic disorders.

Obesity is characterized by an increase in the number or size of fat cells, or both, and is associated with a disruption in the function of adipose tissue. This disruption is marked by adipocyte hypertrophy, impaired lipolysis, and a pro-inflammatory phenotype [10]. Initially obesity was linked to the development of chronic pain, primarily due to both extra mechanical stress on the body and the pro-inflammatory state that it creates, that itself decreases pain threshold to both mechanical and electrical stimuli [13]. At the same time, in patients suffering from chronic pain occurrence of overweight, obesity and even metabolic syndrome is more common [14]. Collectively, these suggest the possibility of a reciprocal effect; however, relatively few studies examine the interrelationships between obesity and pain in a comprehensive manner. There is evidence to suggest that dysregulation of adipocytokine production caused by low-grade inflammation within adipose tissue may also play a role in the pathophysiology of metabolic syndrome [10, 15]. In obese individuals, macrophages infiltrate into adipose tissue causes increased release of pro-inflammatory cytokines including TNF- and IL-6, indicating a link between obesity, inflammation, and insulin resistance [16]. Therefore, gaining an understanding of the signaling pathways by which adipokines regulate metabolism is of paramount importance and to try to develop novel therapies for disorders related to adipose tissue.

Importance of Understanding the Endocrine Aspects of Pain Pathophysiology

Pain is a widespread and debilitating condition that affects millions of people worldwide [17]. The endocrine system, including adipose tissue, plays a vital role in pain perception and modulation. Dysregulation of the endocrine system has been linked to the development of various chronic pain conditions, underscoring the importance of comprehending the interplay between hormones and pain [18]. Moreover, hormone replacement therapy, particularly in postmenopausal women, where estrogen deficiency is associated with an increased risk of chronic pain, may play a significant role in pain management [19‒21].

Therefore, a thorough understanding of the endocrine system’s involvement in pain perception and modulation is critical for the development of more effective pain management strategies. By gaining insight into the complex interplay between hormones and pain, clinicians and researchers can identify specific hormonal pathways involved in pain modulation and develop targeted therapies for pain management. Ultimately, this could help to enhance the quality of life for those living with chronic pain.

Adipose Tissue as an Endocrine Organ

Adipose tissue is traditionally regarded as a site for energy storage in the state of high energy availability. This storage structure, either subcutaneous or visceral, also acts as isolator in regard to heat preservation and provides cushioning in many organs sitting on hard bones. In addition to these rather passive roles, more recently, it recognized that fat tissue is an important endocrine organ. Indeed, fat tissue produces and releases about 600 known bioactive agents with known (patho)physiological actions. The group of various hormones and cytokines are known as adipokines [10, 11]. Adipokines, such as leptin, adiponectin, resistin, visfatin, and asprosin, have different effects on pain perception and modulation, as well as their well-known effects of physiological processes including glucose and lipid metabolism and appetite regulation [10, 11, 22]. The representation of pain modulatory actions of major adipokines on the pathway involved is described in Figure 1.

Adipokines and Pain

Leptin and Pain

Leptin, an adipokine with a molecular weight of 16 kDa, is primarily synthesized by white and brown adipose tissue, regulated by the Lep gene [23]. In addition to adipose tissue, leptin is expressed in various nonadipose tissues. Leptin receptors (OB-R) are present in the hypothalamus, dorsal root ganglion (DRG), heart, liver, small bowel, prostate, and ovary [24‒27]. Leptin plays a critical role in regulating energy homeostasis, neuroendocrine and immune functions, as well as glucose, lipid, and bone metabolism [28, 29]. It exhibits both pro-inflammatory and anti-inflammatory properties [9, 30‒32], influencing systemic inflammation markers and cytokine production that contribute to chronic pain [30, 31, 33]. The involvement of leptin in pain perception and modulation has gained considerable attention [34‒37].

Animal studies provide compelling evidence of leptin’s impact on pain modulation [36, 38‒40]. Leptin affects pain through complex mechanisms, involving both central and peripheral mechanisms [41]. Hu et al. [40] investigated the nociceptive response in obese mice following a high-fat diet. They found that high-fat diet-induced obese mice showed normal thermal pain sensitivity but exhibited attenuated leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3) and lower levels of inflammatory nociceptive responses compared to mice on normal diet. Returning the obese mice to a chow diet for 3 weeks resulted in decreased body weight, body fat, plasma leptin levels, and partial recovery of nociceptive responses. Furthermore, blocking the LEPR pathway or deficiency of LEPR signaling reduced formalin-induced nociceptive responses [40].

In another study, Lim et al. [38] demonstrated that blocking spinal leptin effectively prevented and reversed pain behaviors in a peripheral nerve injury model. They also observed upregulated expression of leptin and its receptors, particularly Ob-Rb, in the spinal cord dorsal horn following nerve injury. Leptin was found to enhance N-methyl-D-aspartate receptor expression and promote interleukin-1 beta (IL-1β) production through the Janus kinase (JAK)/STAT pathway in the spinal cord. Genetic mutations in the leptin gene and exogenous leptin administration abolished and mimicked behavioral and cellular changes associated with nerve injury [38]. Maeda et al. [39] revealed valuable insights into leptin’s role in tactile allodynia. They found that ob/ob mice lacking leptin did not exhibit tactile allodynia after nerve injury. Increased leptin gene transcription was observed in the injured nerve, along with the recruitment of macrophages expressing phosphorylated STAT3 to the injured site. Leptin treatment of macrophages in vitro increased matrix metallopeptidase 9 (MMP-9) and inducible nitric oxide synthase (iNOS) mRNA levels. Administration of leptin-treated peritoneal macrophages reversed the absence of tactile allodynia in ob/ob mice [39].

In human studies, elevated serum leptin levels have been associated with chronic pain conditions such as OA [42], fibromyalgia [43], and migraine [44], while decreased levels have been found in patients with low back pain [45]. Additionally, higher levels of leptin in synovial fluid have been correlated with greater shoulder pain [46]. Leptin may also have an effect on postoperative analgesic need and acute labor pain, with upregulation of serum leptin linked to decreased preoperative pain threshold and increased need of postoperative analgesics [47]. Leptin resistance, occurring in obesity and chronic inflammatory conditions, may contribute to development of increased pain sensitivity by affecting inflammatory pathways [9].

The multifaceted role of leptin in inflammation and the immune system, along with its potential involvement in chronic pain conditions, is an active area of research. Understanding the intricate interplay between leptin, inflammation, and pain could pave the way for targeted therapies in chronic pain management.

Adiponectin and Pain

Adiponectin, a specific protein predominantly synthesized in adipose tissue, exhibits a defined structure consisting of 247 amino acids and molecular weight of approximately 30 kDa in mice and 244 amino acids with a molecular weight of approximately 28 kDa in humans [48‒51]. While adiponectin can permeate the blood-brain barrier, its concentration in the cerebrospinal fluid (CSF) is notably lower, about 100-fold [52]. As a multifaceted adipokine, adiponectin exerts a wide array of effects in various organs and tissues, including the liver, muscle, heart, spinal cord, pituitary gland, and brain. These effects are mediated through the specific binding of adiponectin to its dedicated receptors, namely, adiponectin receptor 1 (AdipoR1) and AdipoR2, which possess a seven-transmembrane domain structure [53‒57]. Remarkably, adiponectin assumes a crucial role in maintaining energy homeostasis by modulating lipid and carbohydrate metabolism, with a notable focus on its profound impact on liver and muscle metabolic processes. Furthermore, adiponectin is recognized for its notable properties, including anti-inflammatory, antithrombotic, anti-atherogenic, anti-apoptotic, and insulin-sensitizing effects [58‒62].

Research performed in animal models highlights analgesic effects of adiponectin [41, 57, 63]. Iannitti et al. [57] conducted a study using a rat model of peripheral inflammation and found that centrally administered adiponectin at the spinal level exerted anti-inflammatory and anti-hyperalgesic effects through its receptors AdipoR1 and AdipoR2. In contrast, peripheral administration of adiponectin, particularly when directly administered into the paw, showed diminished effectiveness. Pre-administration of adiponectin was able to alleviate thermal hyperalgesia induced by carrageenan, while mechanical hypersensitivity and paw edema were unaffected [57]. Furthermore, in context of obese rats with inflammatory hyperalgesia, decreased levels of adiponectin were measured in the spinal cord [41]. Sun et al. [63] conducted a study to explore the impact of adiponectin on thermal nociceptive sensitivity. Their findings indicate that adiponectin may play a role in modulating thermal pain sensitivity by activating the phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and heat-sensitive transient receptor potential cation channel subfamily V member 1 (TRPV1) in both the peripheral and central nervous systems, including DRG neurons, spinal microglia, and somatosensory cortical neurons, following partial sciatic nerve ligation (pSNL) [63]. These findings suggest that adiponectin acts through both peripheral and central mechanism to modulate pain and inflammation.

Dysregulation of serum adiponectin levels has been observed in various clinical conditions, including chronic daily headache [64], variant angina [65] and coronary spastic angina [66], OA pain, and postoperative pain [67]. Furthermore, studies investigating adiponectin levels in different types of headache disorders have reported higher levels of adiponectin in patients with migraine compared to controls [64, 68]. Increased levels of adiponectin in synovial fluid have been associated with greater shoulder pain [46]. These findings suggest a potential involvement of adiponectin dysregulation in the pathophysiology of these conditions, highlighting the role of adiponectin in pain modulation.

Apelin and Pain

Apelin, the endogenous ligand of the orphan APJ receptor, was initially isolated from bovine stomach extracts. The APJ receptor belongs to the G-protein-coupled receptor family [69]. The natural apelin peptide is derived from a precursor protein containing 77 amino acid residues. Through posttranslational processing, the precursor protein is converted into several mature apelin isoforms consisting of varying numbers of amino acid residues, including 12, 13, 15, 16, 17, 19, 28, 31, and 36 [69‒71]. Among these isoforms, apelin-13 exhibits the highest biological potency [72]. Apelin and APJ are expressed in various tissues, including the heart, kidney, liver, gastrointestinal tract, blood vessels, adipose tissue, lung, and brain [73‒79]. A large amount of evidence indicates that the apelin/APJ pathway plays an important role in pathological and physiological processes such as the regulation of cardiovascular function, fluid homeostasis, immune function, gastrointestinal function, and even protecting retinal neuronal cells [70, 80‒85].

The apelin/APJ system has been extensively studied in various pain conditions, including acute pain, inflammatory pain, and neuropathic pain. Current studies investigating the role of apelin-13 in pain have yielded contradictory results, presenting a challenging discrepancy to be resolved. In their respective studies, Xu et al. [86] and Lv et al. [87] investigated the analgesic effects of apelin-13 in mice. Xu et al. [86] demonstrated that apelin-13, when administered intracerebroventricularly, effectively reduced acute thermal pain in mice in a dose- and time-dependent manner. This analgesic effect was attributed to the activation of APJ receptors and subsequent excitation of μ opioid receptors in opioidergic neurons [86]. Similarly, Lv et al. [87] observed significant antinociceptive effects of intracerebroventricular apelin-13 administration on visceral pain in mice. Intrathecal administration of apelin-13 also resulted in a pronounced reduction in nociceptive behavior associated with visceral pain, whereas intraperitoneal injection of apelin-13 did not show an analgesic effect. The involvement of both APJ receptors and μ-opioid receptors was proposed as the underlying mechanism for these effects. Notably, Lv et al. [87] also demonstrated that even a low dose of centrally administered apelin-13 could enhance the analgesic effects of modest doses of morphine at the supraspinal level, even when the initial doses of morphine were ineffective. In another study, chronic intrathecal administration of (Pyr1) apelin-13 was found to alleviate neuropathic pain following compression spinal cord injury in rats [88].

In contrast, Canpolat et al. [89] demonstrated that a single dose of peripherally administered apelin-13 had no significant effect on nociceptive signaling in DRG neurons but caused increased pain sensitivity in an acute pain model. Additionally, Turtay et al. [90] found no discernible difference in the analgesic efficacy between intraperitoneal morphine and apelin-13 in rats, although apelin-13 exhibited a longer duration of analgesia compared to morphine. Interestingly, their study revealed that the co-administration of apelin-13 and ondansetron, a 5-HT3 receptor antagonist, inhibited antinociception, suggesting a potential involvement of 5-HT3 receptors in this modulatory effect. In another study, the combined administration of electroacupuncture and apelin-13 intrathecal injection remarkably exhibited a synergistic antihyperalgesic effect on inflammatory pain in rats. In addition, electroacupuncture treatment attenuated pain behavior and reversed the downregulation of apelin and APJ in the spinal cord [91]. Apelin-13 was found to alleviate capsaicin-induced dental nocifensive behavior and protect against nociception-induced learning and memory impairments via APJ and μ opioid receptors [92]. However, apelin did not play a significant role in regulating the pain threshold in rats with type 1 diabetes mellitus during exercise training [93].

The dual effect of apelin in pain modulation can be influenced by various factors, including injection sites, animal model types, and dosage. Therefore, further investigation is warranted to elucidate the precise mechanisms through which apelin influences pain perception and to explore the potential therapeutic implications of targeting apelin in chronic pain conditions.

Resistin and Pain

Resistin, known as “resistance to insulin,” is a secreted factor primarily expressed in adipose tissue and belongs to the cysteine-rich adipose tissue-specific secretory factor (ADSF) family [94]. The length of the resistin pre-peptide is 108 amino acid residues in humans, while in mice and rats, it consists of 114 amino acids. Encoded by the RETN gene, resistin has a molecular weight of approximately 12.5 kDa [94, 95]. It is mainly produced by adipose tissue and inflammatory cells and functions as a pro-inflammatory adipokine [96].

The exact role of resistin in obesity, insulin sensitivity, and the development of type 2 diabetes mellitus is still up for question, despite the fact that it was first recognized as a factor contributing to the development of insulin resistance and diabetes mellitus in humans [97]. Asthma, inflammatory bowel disease, chronic renal disease, rheumatoid arthritis, malignant neoplasms, atherosclerosis, and cardiovascular disease have all been associated to resistin [98, 99].

Pain has been a central focus in research concerning resistin. It is also worth mentioning that resistin could emerge as a novel biomarker for postoperative pain intensity, although the precise mechanisms behind this relationship remain unclear. There are reports suggesting that serum resistin might be linked to the severity of postoperative pain and could influence the inflammatory status within postoperative wounds [100]. Ictal resistin levels increase with increasing migraine pain severity and decrease following successful acute abortive therapy is in line with the current understanding of resistin’s pro-inflammatory roles and suggests that resistin may also have a pro-inflammatory role in migraine [101].

Resistin, found within the synovial tissue of inflamed joints, has been detected in both RA and OA [102, 103]. Remarkably, resistin’s influence extends to the stimulation of inflammatory cytokines, including IL-6 and TNF-α, alongside the synthesis of PGE2, all of which have implications in the context of pain. These observed effects have given rise to the hypothesis that a decrease in resistin levels might play a contributory role in the pathogenesis and progression of OA [102, 103].

In another notable study led by Sahar Dehghani et al. [104], overweight or obese women with knee OA were the focus as knee pain is a common concern in OA. In this investigation, they introduced a dietary intervention involving a daily 1,000 mg garlic supplement over a span of 12 weeks. Remarkably, this dietary approach led to a reduction in serum resistin concentrations and a significant decrease in pain scores, indicating that pain might be influenced by resistin levels. Intriguingly, this study did not find substantial alterations in TNF-α levels, further highlighting the unique role of resistin in pain modulation. However, it is noteworthy that research conducted by Gandhi et al. [46] suggests that resistin levels in synovial fluid may not be significantly associated with shoulder pain nor do they appear linked to upper extremity pain. These findings add complexity to the relationship between resistin and pain [46].

Visfatin and Pain

Visfatin, first isolated from visceral fat in both humans and mice, shares a close kinship with molecules like pre-B cell colony-enhancing factor (PBEF) and nicotinamide phosphoribosyltransferase (NAMPT). Its structure comprises 491 amino acids (aa) in humans, chimpanzees, cattle, pigs, rats, and mice, with slight variations in other species, such as 490 aa in rhesus monkeys, 285 aa in sheep, 587 aa in opossums, and 588 aa in canines. Beyond its presence in human leukocytes and adipose tissue, visfatin is also expressed in human and animal hepatocytes and muscles [105, 106], as well as in animal adipocytes, kidney, and heart [107‒109]. Visfatin exhibits a multifaceted mode of action, encompassing endocrine, paracrine, and autocrine functions. Visfatin’s versatility enables it to impact diverse processes, including promoting cell proliferation, contributing to nicotinamide mono- and dinucleotide biosynthesis, leading to hypoglycemic effects, and regulating inflammation [108, 110]. Additionally, the noncompetitive anti-visfatin inhibitor FK866 has demonstrated effectiveness in reducing inflammation in various animal models, including spinal cord injury, acute lung injury, and brain injury, by mitigating astrocyte activation, Iba1-positive macrophage/microglia activation, and the inhibition of pro-inflammatory cytokines [111‒114].

With ample evidence pointing toward visfatin as a promising therapeutic target in many types of pain, its multifaceted role in physiology and pathophysiology continues to be a subject of interest and investigation. Notably, Alorfi and Dolan identified visfatin mRNA in spinal cord tissue, while there was no notable change in expression linked to obesity. An increase in visfatin expression was observed in the spinal cord at the 6-h mark following carrageenan-induced inflammation. This increase is believed to stem from the afferent signals originating in the inflamed paw and underscores the complex involvement of visfatin in pain-related processes [115]. Intriguingly, in an experimental model of peripheral neuropathic pain in mice, both serum levels of visfatin and nociception exhibited reductions following treatment with pregabalin [116]. This suggests a potential interplay between visfatin and pain perception, opening new avenues for research into the mechanisms underlying this relationship.

Moreover, it is worth noting that visfatin has demonstrated a pivotal role in all major risk factors and comorbidities associated with OA and OP [117‒122]. Interestingly, there is growing evidence to suggest that visfatin may also be implicated in OA-related pain as it has been shown to induce an increase in mRNA expression and the release of nerve growth factor (NGF) in human and mouse chondrocytes [123]. These multifaceted actions of visfatin underscore its significance in the complex landscape of these conditions.

Asprosin and Pain

Asprosin, a 140-amino acid protein hormone, originates from white adipose tissues in mammals, stimulating the liver to release glucose into the bloodstream [124]. It is cleaved from the C-profibrillin protein encoded by the fibrillin 1 (FBN1) gene, specifically the last two exons (65 and 66). Initially a preproprotein, FBN1 undergoes proteolytic cleavage, producing asprosin and the structural glycoprotein FBN1. In SDS-PAGE, human asprosin runs at approximately 30 kDa, indicating posttranslational modifications, including predicted N-linked glycosylation sites [124]. Asprosin is intricately involved in immune and inflammatory diseases, showing alterations in conditions such as diabetes, obesity, polycystic ovary syndrome, and metabolic syndrome [124, 125]. Asprosin was in fact a CSF protein, in addition to being a plasma protein. Asprosin levels in the CSF of rats were 5- to 10-fold lower than those in the plasma. Additionally, intravenously introduced asprosin showed a dramatic ability to cross the blood-brain barrier and enter the CSF [126]. Asprosin elicits hepatic gluconeogenesis by augmenting cellular cAMP levels, leading to an increase in blood glucose levels [124]; however, its impact on the development of diabetes remains inconclusive [127]. Beyond its gluconeogenic role, asprosin promotes appetite through a cAMP-mediated pathway in animal models [126]. Lee et al. [128] demonstrated that the administration of asprosin induces inflammation and insulin resistance in skeletal muscle. They also found that palmitic acid treatment of mouse insulinoma MIN6 cells and human primary islet cells elevated asprosin expression and secretion. Moreover, it was shown that asprosin promoted the phosphorylation of nuclear factor κB (NF-κB), TNF-α, and monocyte chemoattractant protein-1 (MCP-1), while weakening glucose-stimulated insulin secretion and β-cell activity [123, 126]. Asprosin’s potential involvement in inflammation and immune function suggests a plausible link to the genesis and persistence of chronic pain conditions.

The serum concentration of asprosin serves as a diagnostic tool and a biochemical indicator for assessing mortality and prognosis in individuals experiencing acute chest pain [128]. In our recent investigations, the administration of asprosin demonstrated a notable reduction in both mechanical and thermal hypersensitivity in mouse models, representing various forms of painful neuropathies, including toxic, metabolic, and traumatic origins. Additionally, the levels of asprosin in the animals induced with neuropathic pain were significantly diminished compared to those in healthy mice [129].

Asprosin plays a central role in various physiological and pathological processes. The recent discovery of its involvement in pain modulation, especially in neuropathic conditions, broadens our understanding of its physiological functions. The observed alleviation of hypersensitivity and changes in asprosin levels in pain-related conditions offer promising avenues for exploring its potential in managing chronic pain.

Other Adipokines and Pain

In addition to well-known adipokines, there are emerging evidence that other adipokines are also involved in the process of pain, including omentin, vaspin, and adipsin. Omentin consists of 313 amino acids and was initially identified in a cDNA library from omental fat [130, 131]. It is primarily expressed in visceral adipose tissues, as opposed to subcutaneous adipose tissues [131]. Omentin is also recognized by other names, including endothelial lectin HL-1, intelectin 1, expressed in intestinal Paneth cells [132] and intestinal lactoferrin receptor, found in the small intestine of newborn infants [133]. Circulating levels of omentin-1 were notably reduced in individuals with painful temporomandibular disorders [134]. Additionally, concentrations of omentin-1 in synovial fluid were independently associated with decreased self-reported pain and physical disability in individuals with knee OA [135].

Vaspin, a glycoprotein belonging to the serine protease inhibitor (serpin) family and weighing approximately 47 kDa, has emerged as a significant biomarker. Plasma vaspin notably serves as an effective indicator for assessing the likelihood of future cardiovascular events in individuals experiencing chest pain [136], while also emerging as a marker of musculoskeletal pain disability [137].

Adipsin, also known as complement factor D, serves as a serine protease and a vital component of the alternative complement pathway. Intriguingly, adipsin concentrations have been correlated with back pain, exhibiting this association independently of adiposity in overweight or obese adults [138]. Furthermore, the levels of adipsin have been implicated in the progression of knee OA [139].

The endocrine system plays a critical role in pain perception and modulation, with dysregulation of hormonal pathways contributing to the development and maintenance of chronic pain conditions. Understanding the complex interplay between hormones and pain is essential for the development of more effective pain management strategies. Adipose tissue, a metabolically active organ, produces and releases various hormones and cytokines, known as adipokines, which have different effects on pain perception and modulation. Dysregulation of adipose tissue and adipokines has been linked to the development of chronic pain conditions such as fibromyalgia, OA, and chronic low back pain. Weight loss and pharmacological interventions targeting adipokines and inflammatory cytokines may offer new avenues for pain management. Future research in the area of endocrine and pain pathophysiology may lead to personalized pain management approaches based on individual hormonal profiles and adipose tissue function. Areas for further research include the role of other adipokines in pain, the interaction between adipose tissue and the immune system in pain, and the long-term effects of weight loss and hormone replacement therapy on pain. These areas of investigation may lead to the development of novel targeted therapies for chronic pain conditions, improving the quality of life for those living with chronic pain. Overall, understanding the complex interplay between the endocrine system, adipose tissue, and pain perception and modulation is a crucial area of research that has the potential to revolutionize pain management strategies in the future.

The authors have no conflict or competing interests to declare. Ahmet Ayar is an editorial board member.

No financial support was received from any organization with regard to this work. Both the authors are state university staff and receive salary for their academic position.

M.O. and A.A. contributed to the review design and wrote the manuscript.

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