ca-074-methyl-ester and Chronic-Pain

Interleukin (IL)-1β and IL-18 play critical roles in the induction of chronic pain hypersensitivity. Their inactive forms are activated by caspase-1. However, little is known about the mechanism underlying the activation of pro-caspase-1. There is increasing evidence that cathepsin B (CatB), a typical lysosomal cysteine protease, is involved in the pro-caspase-1 activation and the subsequent maturation of IL-1β and IL-18. In this context, CatB is considered to be an important molecular target to control chronic pain. However, no information is currently available about the role of CatB in chronic pain hypersensitivity. We herein show that CatB deficiency or the intrathecal administration of CA-074Me, a specific CatB inhibitor, significantly inhibited the induction of complete Freund's adjuvant-induced tactile allodynia in mice without affecting peripheral inflammation. In contrast, CatB deficiency did not affect the nerve injury-induced tactile allodynia. Furthermore, CatB deficiency or CA-074Me treatment significantly inhibited the maturation and secretion of IL-1β and IL-18 by cultured microglia following treatment with the neuroactive glycoprotein chromogranin A (CGA), but not with ATP. Moreover, the IL-1β expression in spinal microglia and the induction of tactile allodynia following the intrathecal administration of CGA depended on CatB, whereas those induced by the intrathecal administration of ATP or lysophosphatidic acid were CatB independent. These results strongly suggest that CatB is an essential enzyme for the induction of chronic inflammatory pain through its activation of pro-caspase-1, which subsequently induces the maturation and secretion of IL-1β and IL-18 by spinal microglia. Therefore, CatB-specific inhibitors may represent a useful new strategy for treating inflammation-associated pain.

Topics: Adenosine Triphosphate; Amino Acid Chloromethyl Ketones; Analysis of Variance; Animals; Calcium-Binding Proteins; Carrier Proteins; Cathepsin B; CD11b Antigen; CD4 Antigens; Cells, Cultured; Chromogranin A; Chronic Pain; Cyclooxygenase 2; Dipeptides; Disease Models, Animal; Dose-Response Relationship, Drug; Enzyme Inhibitors; Freund's Adjuvant; Functional Laterality; Ganglia, Spinal; Gene Expression Regulation; Hyperalgesia; Inflammation; Interleukin-18; Interleukin-1beta; Lysophospholipids; Lysosomes; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; Microglia; Motor Activity; Nerve Tissue Proteins; NLR Family, Pyrin Domain-Containing 3 Protein; Pain Threshold; RNA, Small Interfering; Spinal Cord; Transfection