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 B1 (B1R) and B2 (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 14days after EAE immunization. Blockade of B1R significantly suppressed the levels of mRNAs for
IL-17, IFN-γ,
IL-6, CXCL-1/KC, COX-2 and NOS2, as well as glial activation in the spinal cord. Of note, the selective B1 antagonist DALBK consistently prevented IFN-induced up-regulation of TNF-α 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 B1 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, B1 selective antagonists or drugs that reduce
kinin release may have the potential to treat
neuropathic pain in patients suffering from MS.