Prokineticin System Is a Pharmacological Target to Counteract Pain and Its Comorbid Mood Alterations in an Osteoarthritis Murine Model

Abstract

Osteoarthritis (OA) is the most prevalent joint disease associated with chronic pain. OA pain is often accompanied by mood disorders. We addressed the role of the Prokineticin (PK) system in pain and mood alterations in a mice OA model induced with monosodium iodoacetate (MIA). The effect of a PK antagonist (PC1) was compared to that of diclofenac. C57BL/6J male mice injected with MIA in the knee joint were characterized by allodynia, motor deficits, and fatigue. Twenty-eight days after MIA, in the knee joint, we measured high mRNA of PK2 and its receptor PKR1, pro-inflammatory cytokines, and MMP13. At the same time, in the sciatic nerve and spinal cord, we found increased levels of PK2, PKR1, IL-1β, and IL-6. These changes were in the presence of high GFAP and CD11b mRNA in the sciatic nerve and GFAP in the spinal cord. OA mice were also characterized by anxiety, depression, and neuroinflammation in the prefrontal cortex and hippocampus. In both stations, we found increased pro-inflammatory cytokines. In addition, PK upregulation and reactive astrogliosis in the hippocampus and microglia reactivity in the prefrontal cortex were detected. PC1 reduced joint inflammation and neuroinflammation in PNS and CNS and counteracted OA pain and emotional disturbances.

The Prokineticin System in Inflammatory Bowel Diseases: A Clinical and Preclinical Overview

“…Subsequent studies supported the PKS's physiological role in nociception, as PKR and PK2 KO mice were less sensitive to noxious stimuli than wildtype (WT) mice, with less hyperalgesia onset after tissue damage [87][88][89][90]. A role of the PKS has also been demonstrated in the development and maintenance of both chronic inflammatory [91,92] and neuropathic pain of various etiologies [93][94][95][96][97][98][99][100][101]. In these studies, it has been well demonstrated that the presence of aberrant pain was associated with an upregulation in PK2 and PKRs, and that selective PKS antagonism was able to counteract pain symptoms and neuroinflammation.…”