The role of kinin B1 and B2 receptors in the persistent pain induced by experimental autoimmune encephalomyelitis (EAE) in mice: Evidence for the involvement of astrocytes

Multiple sclerosis (MS) is a progressive, demyelinating inflammatory disease of the human central nervous system (CNS). While the primary symptoms of MS affect motor function, it is now recognized that chronic pain is a relevant symptom that affects both animals and MS patients. There is evidence that glial cells, such as astrocytes, play an important role in the development and maintenance of chronic pain. Kinins, notably bradykinin (BK) acting through B-1 (B1R) and B-2 (B2R) receptors, play a central role in pain and inflammatory processes. However, it remains unclear whether kinin receptors are involved in neuropathic pain in MS. Here we investigated by genetic and pharmacological approaches the role of kinin receptors in neuropathic pain behaviors induced in the experimental autoimmune encephalomyelitis (EAE) mouse model. Our results showed that gene deletion or antagonism of kinin receptors, especially B1R, significantly inhibited both tactile and thermal hypersensitivity in EAE animals. By contrast, animals with EAE and treated with a B1R selective agonist displayed a significant increase in tactile hypersensitivity. We also observed a marked increase in B1R mRNA and protein level in the mouse spinal cord 14 days after EAE immunization. Blockade of B1R significantly suppressed the levels of mRNAs for IL-17, IFN-gamma, IL-6, CXCL-1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B-1 antagonist DALBK consistently prevented IFN-induced up-regulation of TNF-alpha and IL-6 release in astrocyte culture. Finally, both B1R and B2R antagonists significantly inhibited COX-2 and NOS2 expression in primary astrocyte culture. The B1R was co-localized with immunomarker of astrocytes in the spinal cord of EAE-treated animals. The above data constitute convincing experimental evidence indicating that both kinin receptors, especially the B-1 subtype, exert a critical role in the establishment of persistent hypersensitivity observed in the EAE model, an action that seems to involve a central inflammatory process, possibly acting on astrocytes. Thus, B-1 selective antagonists or drugs that reduce kinin release may have the potential to treat neuropathic pain in patients suffering from MS. (C) 2013 Elsevier Inc. All rights reserved.