Chronic pelvic pain is generally defined by chronic pain in the region of the pelvis (1). It is a common symptom of several structural and functional disorders affecting the anorectal area, urinary bladder, reproductive system, and pelvic floor musculature and its innervation (2). In contrast to structural diseases such as endometriosis, the pelvic pain in functional disorders cannot be explained by an organic or other specified morphological pathology (3). Functional disorders are classified into anorectal (e.g., proctalgia fugax, levator anisyndrome, and unspecified anorectal pain), bladder [e.g., interstitial cystitis (IC)/bladder pain syndrome], and prostate syndromes [e.g., chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)]. IC/bladder pain syndrome is primarily diagnosed in women, whereas CP/CPPS is a diagnosis exclusive to men. Although IC and CP/CPPS have been largely considered different, they share many clinical features and are currently classified under the umbrella term, urologic chronic pelvic pain syndromes (4).

Chronic pelvic pain experienced by patients bearing CP/CPPS presents as chronic pain (that lasts for at least 3–6 months) in the region of the pelvis, perineum, scrotum, rectum, testes, penis, and often associated to ejaculatory pain, pain in lower back and abdomen, often associated to lower urinary tract symptoms, erectile dysfunction, and psychosocial symptoms. Lower urinary tract symptoms may include obstructive and/or irritative voiding symptoms. Erectile dysfunction is a major concern for CP/CPPS patients, which is defined as the persistent inability to attain and maintain a penile erection that is sufficient for satisfactory sexual performance (5). All these complaints lead to patient frustration, diminished quality of life as well as impairments in primary intimate relationships. Moreover, there is a common association of CP/CPPS with other systemic syndromes such as irritable bowel syndrome, fibromyalgia, cardiovascular disease, stress, depression, and anxiety (6). In fact, in terms of pain and deteriorated quality of life, CP/CPPS patients have shown to have a quality of life comparable with that of patients who have suffered myocardial infarction or bear Crohn disease (7).

The term prostatitis defines as a state of inflammation of the prostate gland. The currently used classification of prostatitis was proposed by the National Institutes of Health (NIH) in 1999 (8). Prostatitis syndromes are divided in four categories: acute and chronic bacterial prostatitis (types I and II), CP/CPPS (type III), and asymptomatic inflammatory prostatitis (type IV). Acute and chronic bacterial prostatitis are characterized by uropathogenic infections in which causative pathogens can be detected in the semen, in expressed prostate secretions (EPS), or urine after prostatic massage; and these infections respond well to antibiotic therapy (9, 10). In contrast, CP/CPPS or NIH type III prostatitis is a complex and frustrating disease for both, patients and physicians, with symptoms that are difficult to quantify as well as to effectively treat. CP/CPPS is defined by chronic pelvic pain and signs and symptoms of prostate inflammation, lasting for at least 3–6 months, in the absence of any detectable infection. These features distinguish it from the other types of prostatitis (11, 12). CP/CPPS presents with a mixture of chronic pelvic pain, lower urinary tract symptoms, and ejaculatory/sexual complaints with no uniformly effective therapy (6, 13). Noteworthy, CP/CPPS is one of the most common diseases frequently diagnosed in the fields of urology and andrology (10). Moreover, it has been revealed that CP/CPPS may have significant consequences in male fertility (10, 14). It accounts for more than 90% of all cases of prostatitis diagnosed and it has been estimated that affects 9–16% of men of all ethnic origins and is the most common urologic morbidity in men younger than 50 years old (15–17).

Chronic prostatitis/chronic pelvic pain syndrome is a syndrome, thus patients may be very heterogeneous and present a widely variable array of symptoms. In response to that, two multimodal approach systems are currently used to assess CP/CPPS symptom severity and to help physicians to manage patients: the CP Symptom Index from the NIH (NIH-CPSI) and the urinary, psychosocial, organ specificity, infection, neurologic, and tenderness (UPOINT) system (18, 19). On the one hand, the NIH-CPSI intends to assess symptoms severity and to quantify their impact on the patients’ quality of life. However, it should be noted that is generally based on a subjective questionnaire and overall scores are determined by a cumulative scoring of symptoms that might and might not be related to one another, or indeed to the underlying causes of pathology. The NIH-CPSI is a validated nine question survey that covers the following three domains: pain (location, frequency, and severity), urinary symptoms, and quality of life (18). Using this system, CP/CPPS is diagnosed when patients present with pelvic pain and an index score higher than 4. A six-point improvement in total score is considered clinically significant correlates with patient reported improvement (20). On the other hand, the UPOINT system can be used to identify clinical phenotypes and can also be used to direct therapy. This system considers each group of patients’ symptoms and divides them into six categories: urinary, psychosocial, organ specificity symptoms, infection, neurologic/systemic, and tenderness. The characteristics and advantages of this classification system and its implications in therapy prescription were excellently analyzed in a recent review by Polackwich and Shoskes (6). As a reflex of the diversity of patients’ symptoms, the median number of positive UPOINT domains is 3 and only 22% of patients have a single positive domain. In addition, UPOINT domains involved have been shown to correlate with NIH-CPSI scores (21, 22), and also help in guiding the practitioner to prescribe therapy. The use of this system treatment strategy is starting to become more widespread and is proving its effectiveness significantly improving the patients’ quality of life (23, 24).

Available therapeutic options for CP/CPPS are far from satisfactory for either physicians or patients. A novel, effective therapeutic approach is urgently needed (6, 25, 26). The main reason for the lack of effective and uniform therapies is that the etiology of CP/CPPS still remains unknown (27). Most likely, CP/CPPS comprises similar clinical phenotypes resultant from a combination of different pathophysiological mechanisms. During the last two decades, research in the field has experienced a notable growth. Several hypotheses have been proposed to explain CP/CPPS pathogenesis including defective urothelial integrity and function, cryptic infections, autoimmunity, endocrine imbalances, pelvic floor muscle spasm or tenderness, voiding dysfunction, peripheral and central sensitization and neuroplasticity, and psychosocial conditions (1, 2).

One of the main and currently unanswered questions in CP/CPPS is how chronic pelvic pain develops and whether a mechanistic link with inflammation exists. Due to the unknown pathophysiological pain mechanisms involved and to the diverse range of symptoms, both in type and severity, presented by patients, no standard, and completely effective therapeutic approach exists. Wide ranges of therapies for pain control have been tested, but most have shown heterogeneous efficiency, particularly in pain management (27).

As for any organ system, male pelvic pain occurs as a physiological alarm to withdraw from an injurious (infectious, irritative, inflammatory, or traumatic) condition to reduce tissue damage (100). However, chronic pain may start after tissue damage or inflammation and remain subsequent to tissue healing, becoming harmful, and detrimental to health (101). Chronic pain is commonly triggered by chronic peripheral inflammation and nerve injury. These results in the release of neurotransmitters, lipid mediators, fragments of the complement system, neuropathic factors, cytokines, and chemokines in both the central and peripheral nervous system (101). Both, inflammatory and neuropathic pain can cause peripheral and central sensitization that can lead to allodynia, hyperalgesia, and spontaneous pain. Several authors specialized in this area suggest that inflammatory/neuropathic pain may play a central role in CP/CPPS (17, 33, 100, 102). Chronic pelvic pain include a combination of spontaneous visceral and referred somatic pain characteristics (i.e., pelvic visceral and referred perineal pain), and also the involvement of central sensitization in the spinal cord and brain (103). CP/CPPS patients have shown specific patterns of functional and pain-related brain activation and anatomical reorganization, which correlated with clinical pain intensity (104, 105). These changes were evident in regional and global scales, suggesting an ongoing reorganization of brain circuitry similar to other chronic pain morbidities such as musculoskeletal and neuropathic pain, chronic low back pain, postherpetic neuralgia, complex regional pain syndrome, and knee osteoarthritis (106). These findings suggest that the chronic presence of pelvic pain leaves specific brain neural imprints that persist for years. Alternatively, some of these neural abnormalities may be predisposing factors for CP/CPPS. However, it is unclear if these central changes are the cause or consequences of disease progression.

Although thalamic and brain cortical levels may be involved in pelvic pain in CP/CPPS, most attention has focused on the dorsal horn of the spinal cord. Central sensitization is caused by chemical and anatomical changes leading to hyperexcitability in the dorsal horn cells from persistent afferent C fiber bombardment by painful stimuli (102). Chronic pain is induced and maintained by mediators released by immune cells (macrophages, lymphocytes, and mast cells), neurons and glial cells that trigger peripheral and central sensitization (107). It has been proposed that neurogenic processes, autoimmune injury, and mast cells may contribute to inflammation and trigger pain development in CP/CPPS in males (108). Inflammatory stimuli are known to induce SP, calcitonin gene-related peptide, and nerve growth factor (NGF) secretion from nerve terminals, resulting in plasma extravasation, edema, and hyperalgesia, commonly referred to as neurogenic inflammation (109). Interestingly, animal models of prostate inflammation and pain have shown that chemokines and cytokines are crucial in sustaining or amplifying inflammation induced by SP (110, 111). In this regard, mast cells have been suggested to play a central role (109). Increased number of mast cells and their secretion products has been associated with chronic inflammatory pain conditions such as rheumatoid arthritis, multiple sclerosis, IC, and inflammatory bowel disease (109, 112–117). They are currently suggested as the main mediator and effector cells in disease progression from initiation to breaking of tolerance, neuronal activation, and, eventually, sensitization (109, 118, 119). Mast cells are tissue-resident immune cells that promote the infiltration of inflammatory cells such as macrophages and lymphocytes into tissues, which when activated secrete cytokines that further activate mucosal mast cells, thus perpetuating the cycle of inflammation. Moreover, mast cells respond to SP and NGF secreted by neuronal terminals degranulating and releasing histamine, serotonin, cytokines, chemokines, prostaglandins, and neuropeptides such as brain-derived neurotrophic factor, neurotrophin-3, and more NGF and SP (120, 121). Mast cells are known to express NGF receptors (TrkA, B, C) on their cell membrane and, therefore, NGF binding might cause degranulation and cytokine and chemokine release, establishing a feedback mechanism that would promote rapidly occurring sensitization mechanisms (121). The augmented density of sensory nerve fibers observed in prostatitis (72, 73) and inflammation induced by mast cell activation and degranulation might result in irreversibly altered neurotransmission and thus explain, at least partly, the chronic nature of pain in CP/CPPS. It has been shown that CP/CPPS patients have elevated levels of mast cell attractant chemokines CCL2 (MCP-1) and CCL3 (MIP-1α) in EPS, which associated with clinical pain (59). Moreover, elevated levels of mast cell tryptase-β, carboxypeptidase A3, and NGF were also detected in EPS and urine from CP/CPPS patients, and those NGF levels directly correlated with pain severity (70, 71, 122). These results suggest that NGF and mast cells secretion products are potential mediators involved in pain sensitization mechanisms in CP/CPPS. In agreement, treatment with pentosan polysulfate, a stabilizer of mast cells was shown to ameliorate symptoms in CP/CPPS patients (123). Besides, tanezumab, a monoclonal antibody against NGF, was evaluated for CP/CPPS treatment. However, clinical trials showed no significant improvement compared with placebo suggesting that anti-NGF therapy is not sufficient by itself to reduce symptoms (124).

The presence of markedly increased numbers of mast cells in prostate cell infiltrates was already reported in animal models of autoimmune prostatitis several years ago (125–129). Moreover, adoptive transfer of lymphocytes from animals with prostatitis to naïve recipients caused disease inducing prostate inflammation in terms of lymphocytic infiltration and the presence of mast cells (127) (Table 1). Furthermore, mast cells evidenced an activated state since most of them showed to be degranulated (21, 125–127, 129) and having secreted pain inducer molecules such as NGF and tryptase-β (70, 71). It has been shown that NGF sensitizes sympathetic neurons to proinflammatory stimuli (130). In fact, mice with EAP showed increased intraprostatic NGF levels, augmented neuronal density in prostate tissue, and also microglial activation in the spinal cord (71–73, 131). As observed in patients, increased levels of CCL2 and CCL3 were also demonstrated in EAP, which were suggested to play a major role in recruiting mast cells and mediating pain (60). In addition, mast cell-deficient Kit^W-sh/Kit^W-sh mice have significantly decreased intraprostatic NGF levels and attenuated pain responses upon EAP induction (71). Cytokines secreted by mast cells have been shown to control Th17/Treg cell differentiation and plasticity (132). In this regard, Murphy et al. recently provided some controversial evidence indicating that IL-17 would be crucial for the induction but not maintenance of pelvic pain in EAP in C57BL/6 mice (64). Authors showed that prophylactic treatment with IL-17-blocking antibodies was sufficient to abolish pelvic pain development. However, they surprisingly did not show any data about prostate tissue inflammation or cell infiltration in order to definitively assess if pelvic pain was related to prostate inflammation. Besides, the authors remarkably showed that they failed in preventing or ameliorating chronic pelvic pain when administering a therapeutic treatment of IL-17-blocking antibodies on day 10 post EAP induction (64). In order to definitely assess the role of IL-17 in mediating chronic pelvic pain, we recently analyzed pelvic pain development and prostate inflammation induction in EAP using IL-17A/F-double KO and wild type (C57BL/6) mice (67). Our results demonstrated that wild type mice induced prostate-specific Th1 and Th17 immune responses that caused prostate tissue inflammation and chronic pelvic pain development, which augmented as disease progressed, suggesting that chronic pelvic pain development was a consequence of prostate inflammation. Interestingly, IL-17A/F-double KO mice induced a prostate-specific immune response, prostate tissue inflammation, and chronic pelvic pain development similar to wild type mice (67). Therefore, IL-17 was shown to be dispensable for prostate inflammation induction and chronic pelvic pain development. Furthermore, similar levels of mast cell infiltrates, in close contact to nerve fibers, were observed in IL-17A/F-double KO and wild type mice (unpublished data), in agreement with the similar pattern of chronic pelvic pain development and as previously reported (133). In summary, development of chronic pelvic pain was only shown in those animals that induced prostate-specific Th1 immune responses and subsequently prostate tissue inflammation, cell infiltration, and mast cell recruitment. In fact, PAg-specific Th1 cells express associated chemokine receptors such as CXCR3 and CCR5 and migrate to and infiltrate the prostate gland (66). Once there, these lymphocytes induce the local secretion of several cytokines and chemokines, including the ligands for CXCR3 and CCR5, which in turn recruit more leukocytes augmenting tissue cell infiltration and enhancing prostate inflammation and chronic pelvic pain development (62, 65, 66, 68, 69). Altogether, these evidence support the notion that within the Th1 induced leukocyte infiltrates, mast cells might be key actors in the consequent development of chronic pelvic pain (Figure 1). However, it remains to be established if removal of inflammation can reverse or ameliorate mast cell infiltration, neuronal sensitization, and chronic pelvic pain. Additional studies are needed to establish the relationship between prostatitis induction, prostate mast cell activation/degranulation, and the precise mechanisms by which they would induce chronic pelvic pain.

Chronic prostatitis/chronic pelvic pain syndrome is a complex and frustrating syndrome because of the unknown underlying pathophysiological mechanisms and the lack of appropriate and effective therapies. The emergence of interest and new research on the field has allowed a significant improvement in the understanding of this syndrome. Data obtained from studies in patients and animal models have confirmed the involvement of immune mechanisms in the etiology, pathogenesis, and chronic pelvic pain development. Several factors may trigger chronic inflammation in the form of autoimmunity directed against PAg and foster chronic prostate inflammation with the recruitment of different leukocytes including mast cells. The local inflammatory milieu and the secretion of inflammatory mediators may induce neural sensitization leading to chronic pelvic pain development (Figure 1). Further study of the available experimental animal models together with more extensive research in the human syndrome will shed light on the precise physiopathology of CP/CPPS, something that in turn may help in finding more rational and effective therapies.

All authors have contributed to the conception, design, drafting, and revision of the work, provided important intellectual content; and carefully reviewed and approved the final version of the manuscript. Authors agree to be accountable for all aspects of the work, in terms of accuracy or integrity and other related aspects.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.