a-803467 and Chronic-Pain

Essentials The role of platelet P2Y. Background P2Y

Topics: Adenosine Monophosphate; Aniline Compounds; Animals; Blood Platelets; Chemokine CXCL1; Chronic Pain; Cytokines; Freund's Adjuvant; Furans; Hyperalgesia; Inflammation; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Pain; Receptors, Purinergic P2Y12; Time Factors; Tumor Necrosis Factor-alpha

Chronic pelvic pain (CPP) is a high burden for patients and society. It affects 15-24% of women in reproductive age and is an area of high unmet medical need. CPP can be caused by a wide range of visceral diseases such as abdominal infections, gastrointestinal or gynaecological diseases like endometriosis. Despite the high medical need for this condition, pharmacological approaches are hampered by the limited number of available methods for the behavioural evaluation of pain in inflammation-driven animal models of pelvic pain.. The dynamic weight bearing (DWB) system was used for the evaluation of spontaneous behaviour changes in the zymosan-induced peritonitis mouse model. Inflammatory mediator levels were evaluated in peritoneal lavage and their correlation with the behavioural endpoints was assessed. We evaluated the effect on behavioural endpoints of the selective cyclooxygenase-2 (COX-2) inhibitor celecoxib and the Nav 1.8 blocker A-803467.. The presence of a relief posture, characterized by a significantly increased weight distribution towards the front paws, was observed following intraperitoneal injection of zymosan. A positive correlation was detected between PGE2 levels in the peritoneal lavage and DWB endpoints. In addition, zymosan-induced weight bearing changes were reverted by celecoxib and A-803467.. This study described for the first time the use of DWB as a non-subjective and non-reflexive method for the evaluation of inflammatory-driven abdominal pain in a mouse model.

Topics: Abdominal Pain; Aniline Compounds; Animals; Behavior, Animal; Celecoxib; Chronic Pain; Cyclooxygenase 2 Inhibitors; Dinoprostone; Disease Models, Animal; Furans; Inflammation; Mice; Pain Measurement; Pelvic Pain; Peritoneal Lavage; Peritonitis; Sodium Channel Blockers; Weight-Bearing; Zymosan

Tissue acidosis is effective in causing chronic muscle pain. However, how muscle nociceptors contribute to the transition from acute to chronic pain is largely unknown.. Here we showed that a single intramuscular acid injection induced a priming effect on muscle nociceptors of mice. The primed muscle nociceptors were plastic and permitted the development of long-lasting chronic hyperalgesia induced by a second acid insult. The plastic changes of muscle nociceptors were modality-specific and required the activation of acid-sensing ion channel 3 (ASIC3) or transient receptor potential cation channel V1 (TRPV1). Activation of ASIC3 was associated with increased activity of tetrodotoxin (TTX)-sensitive voltage-gated sodium channels but not protein kinase Cϵ (PKCϵ) in isolectin B4 (IB4)-negative muscle nociceptors. In contrast, increased activity of TTX-resistant voltage-gated sodium channels with ASIC3 or TRPV1 activation in NaV1.8-positive muscle nociceptors was required for the development of chronic hyperalgesia. Accordingly, compared to wild type mice, NaV1.8-null mice showed briefer acid-induced hyperalgesia (5 days vs. >27 days).. ASIC3 activation may manifest a new type of nociceptor priming in IB4-negative muscle nociceptors. The activation of ASIC3 and TRPV1 as well as enhanced NaV1.8 activity are essential for the development of long-lasting hyperalgesia in acid-induced, chronic, widespread muscle pain.

Topics: Acid Sensing Ion Channels; Acute Pain; Aniline Compounds; Animals; Cells, Cultured; Chronic Pain; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fibromyalgia; Furans; Ganglia, Spinal; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Muscle, Skeletal; NAV1.8 Voltage-Gated Sodium Channel; Sodium Channel Blockers; TRPV Cation Channels