Physiological Changes and Pathological Pain Associated with Sedentary Lifestyle-Induced Body Systems Fat Accumulation and Their Modulation by Physical Exercise

A sedentary lifestyle is associated with overweight/obesity, which involves excessive fat body accumulation, triggering structural and functional changes in tissues, organs, and body systems. Research shows that this fat accumulation is responsible for several comorbidities, including cardiovascular, gastrointestinal, and metabolic dysfunctions, as well as pathological pain behaviors. These health concerns are related to the crosstalk between adipose tissue and body systems, leading to pathophysiological changes to the latter. To deal with these health issues, it has been suggested that physical exercise may reverse part of these obesity-related pathologies by modulating the cross talk between the adipose tissue and body systems. In this context, this review was carried out to provide knowledge about (i) the structural and functional changes in tissues, organs, and body systems from accumulation of fat in obesity, emphasizing the crosstalk between fat and body tissues; (ii) the crosstalk between fat and body tissues triggering pain; and (iii) the effects of physical exercise on body tissues and organs in obese and non-obese subjects, and their impact on pathological pain. This information may help one to better understand this crosstalk and the factors involved, and it could be useful in designing more specific training interventions (according to the nature of the comorbidity).

Investigating the Function of Adult DRG Neuron Axons Using an In Vitro Microfluidic Culture System

A critical role of the peripheral axons of nociceptors of the dorsal root ganglion (DRG) is the conduction of all-or-nothing action potentials from peripheral nerve endings to the central nervous system for the perception of noxious stimuli. Plasticity along multiple sites along the pain axis has now been widely implicated in the maladaptive changes that occur in pathological pain states such as neuropathic and inflammatory pain. Notably, increasing evidence suggests that nociceptive axons actively participate through the local expression of ion channels, receptors, and signal transduction molecules through axonal mRNA translation machinery that is independent of the soma component. In this report, we explore the sensitization of sensory neurons through the treatment of compartmentalized axon-like structures spanning microchannels that have been treated with the cytokine IL-6 and, subsequently, capsaicin. These data demonstrate the utility of isolating DRG axon-like structures using microfluidic systems, laying the groundwork for constructing the complex in vitro models of cellular networks that are involved in pain signaling for targeted pharmacological and genetic perturbations.

Eliapixant is a selective P2X3 receptor antagonist for the treatment of disorders associated with hypersensitive nerve fibers

ATP-dependent P2X3 receptors play a crucial role in the sensitization of nerve fibers and pathological pain pathways. They are also involved in pathways triggering cough and may contribute to the pathophysiology of endometriosis and overactive bladder. However, despite the strong therapeutic rationale for targeting P2X3 receptors, preliminary antagonists have been hampered by off-target effects, including severe taste disturbances associated with blocking the P2X2/3 receptor heterotrimer. Here we present a P2X3 receptor antagonist, eliapixant (BAY 1817080), which is both highly potent and selective for P2X3 over other P2X subtypes in vitro, including P2X2/3. We show that eliapixant reduces inflammatory pain in relevant animal models. We also provide the first in vivo experimental evidence that P2X3 antagonism reduces neurogenic inflammation, a phenomenon hypothesised to contribute to several diseases, including endometriosis. To test whether eliapixant could help treat endometriosis, we confirmed P2X3 expression on nerve fibers innervating human endometriotic lesions. We then demonstrate that eliapixant reduces vaginal hyperalgesia in an animal model of endometriosis-associated dyspareunia, even beyond treatment cessation. Our findings indicate that P2X3 antagonism could alleviate pain, including non-menstrual pelvic pain, and modify the underlying disease pathophysiology in women with endometriosis. Eliapixant is currently under clinical development for the treatment of disorders associated with hypersensitive nerve fibers.

Neurogenesis in the adult brain functionally contributes to the maintenance of chronic neuropathic pain

Maladaptive adult neurogenesis in the mammalian brain has been associated with diverse behaviors including disrupted learning, negative mood disorders and psychiatric conditions. However, its functional role in the generation and maintenance of chronic pathological pain has not yet been elucidated. Using an inducible genetic deletion in vivo mouse model, different behavioural paradigms and home cage monitoring systems, we show that an absence of adult neurogenesis does not impact the development of neuropathic injury-induced peripheral nociceptive hypersensitivity, but rather promotes the recovery of pathological pain as well as improves parameters associated with the state of well-being of the injured mice. These results provide a mechanistic insight into the mechanisms of chronic pain and implicate neurogenic processes as a potential therapeutic target for reducing pain and improving the quality of life for patients.

Electroacupuncture inhibits the interaction between peripheral TRPV1 and P2X3 in rats with different pathological pain

Chronic pain is regarded to be one of the common and refractory diseases to cure in the clinic. One hundred Hz electroacupuncture (EA) is commonly used for inflammatory pain and 2 Hz for neuropathic pain possibly by modulating the transient receptor potential vanilloid subtype 1 (TRPV1) or the purinergic P2X3 related pathways. To clarify the mechanism of EA under various conditions of pathological pain, rats received a subcutaneous administration of complete Freund’s adjuvant (CFA) for inflammatory pain and spared nerve injury (SNI) for neuropathic pain. The EA was performed at the bilateral ST36 and BL60 1 d after CFA or SNI being successfully established for 3 consecutive days. The mechanical hyperalgesia test was measured at baseline, 1 d after model establishment, 1 d and 3 d after EA. The co-expression changes, co-immunoprecipitation of TRPV1 and P2X3, and spontaneous pain behaviors (SPB) test were performed 3 d after EA stimulation. One hundred Hz EA or 2Hz EA stimulation could effectively down-regulate the hyperalgesia of CFA or SNI rats. The increased co-expression ratio between TRPV1 and P2X3 at the dorsal root ganglion (DRG) in two types of pain could be reduced by 100Hz or 2Hz EA intervention. While 100Hz or 2Hz EA was not able to eliminate the direct physical interaction between TRPV1 and P2X3. Moreover, EA could significantly inhibit the SPB induced by the co-activation of peripheral TRPV1 and P2X3. All results indicated that EA could significantly reduce the hyperalgesia and the SPB, which was partly related to inhibiting the co-expression and indirect interaction between peripheral TRPV1 and P2X3.

Efficacy of Acupuncture on Pain Mechanisms, Inflammatory Responses, and Wound Healing in the Acute Phase of Major Burns: An Experimental Study on Rats

Objectives We investigated acupuncture, a potential contributor for burn-care, on physiological and pathological pain mechanisms and systemic and local inflammatory responses in a rat experimental burn model. Methods Forty male Sprague-Dawley rats were divided into 2 groups. One-hour groups(5 rats/group) were observed for 1 hour and included Sh1(sham/observation), ShA1(sham+acupuncture/observation), Brn1(burn/observation), and BrnA1(burn+acupuncture/observation). Seven-day groups(5 rats/group) were observed for 7 days and included Sh7(sham/observation), ShA7(sham+acupuncture/observation), Brn7(burn/observation), and BrnA7(burn+acupuncture/observation). “Pain-distress scores” were noted daily, acupuncture was repeated within every wound-dressing change on alternate days. After observation periods, blood samples for interleukin-6 and beta-endorphin and skin biopsies for inflammatory-changes and immunohistochemical-staining of interleukin-6 were collected for analysis( P< .05 ). Results In 1-hour groups, interleukin-6 accumulation in burn wounds of BrnA1 was less than Brn1, with Brn1 having the highest mean blood level(P< .05). Mean beta-endorphin levels were higher in ShA1, Brn1, and BrnA1 than in Sh1(P< .05). In all 7-day groups, the agonizing period was 48 to72 hours after burn, with Brn7 most affected(P< .05). Microvessels were multiplied in Brn7group, with significantly higher numbers in burn wounds of BrnA7(P˂ .05). Burn wounds of BrnA7 had less accumulation of interleukin-6 than Brn7 with Brn7-group having the highest mean blood level and Sh7, ShA7, and BrnA7 having similarly low levels(P˃ .05). Beta-endorphin levels in ShA7, Brn7, and BrnA7 were lower than in Sh7(P< .05). Conclusions Acupuncture contributed to management of physiological and pathological pain, modulation of inflammatory responses, and associated enhancement of angiogenesis in acute phase of burn injury in rats.

Macrophage as a Peripheral Pain Regulator

A neuroimmune crosstalk is involved in somatic and visceral pathological pain including inflammatory and neuropathic components. Apart from microglia essential for spinal and supraspinal pain processing, the interaction of bone marrow-derived infiltrating macrophages and/or tissue-resident macrophages with the primary afferent neurons regulates pain signals in the peripheral tissue. Recent studies have uncovered previously unknown characteristics of tissue-resident macrophages, such as their origins and association with regulation of pain signals. Peripheral nerve macrophages and intestinal resident macrophages, in addition to adult monocyte-derived infiltrating macrophages, secrete a variety of mediators, such as tumor necrosis factor-α, interleukin (IL)-1β, IL-6, high mobility group box 1 and bone morphogenic protein 2 (BMP2), that regulate the excitability of the primary afferents. Neuron-derived mediators including neuropeptides, ATP and macrophage-colony stimulating factor regulate the activity or polarization of diverse macrophages. Thus, macrophages have multitasks in homeostatic conditions and participate in somatic and visceral pathological pain by interacting with neurons.

Tetrodotoxin, a Potential Drug for Neuropathic and Cancer Pain Relief?

Tetrodotoxin (TTX) is a potent neurotoxin found mainly in puffer fish and other marine and terrestrial animals. TTX blocks voltage-gated sodium channels (VGSCs) which are typically classified as TTX-sensitive or TTX-resistant channels. VGSCs play a key role in pain signaling and some TTX-sensitive VGSCs are highly expressed by adult primary sensory neurons. During pathological pain conditions, such as neuropathic pain, upregulation of some TTX-sensitive VGSCs, including the massive re-expression of the embryonic VGSC subtype NaV1.3 in adult primary sensory neurons, contribute to painful hypersensitization. In addition, people with loss-of-function mutations in the VGSC subtype NaV1.7 present congenital insensitive to pain. TTX displays a prominent analgesic effect in several models of neuropathic pain in rodents. According to this promising preclinical evidence, TTX is currently under clinical development for chemo-therapy-induced neuropathic pain and cancer-related pain. This review focuses primarily on the preclinical and clinical evidence that support a potential analgesic role for TTX in these pain states. In addition, we also analyze the main toxic effects that this neurotoxin produces when it is administered at therapeutic doses, and the therapeutic potential to alleviate neuropathic pain of other natural toxins that selectively block TTX-sensitive VGSCs.