Abstract
Previous studies have demonstrated that the red nucleus (RN) participates in the modulation of neuropathic pain and plays both a facilitated role by pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), and an inhibitory role through the anti-inflammatory cytokine IL-10. In this study, we sought to investigate the expressions and roles of transforming growth factor-beta (TGF-β), a potent anti-inflammatory cytokine, as well as its type 1 receptor (TGF-β-R1) in the RN in normal and neuropathic pain rats. Immunohistochemistry showed that TGF-β and TGF-β-R1 were constitutively expressed in the RN of normal rats, and co-localized with neurons and all three glial cell types, astrocytes, microglia and oligodendrocytes. Following spared nerve injury (SNI), the expression levels of TGF-β and TGF-β-R1 were significantly down-regulated in the RN contralateral (but not ipsilateral) to the nerve injury side of rats at one week and reached the lowest level at two weeks after SNI, and both of them were co-localized with neurons and oligodendrocytes but not with astrocytes and microglia. Microinjection of different doses of anti-TGF-β antibody (250, 125, 50ng) into the unilateral RN of normal rats dose-dependently decreased the mechanical withdrawal threshold of contralateral (but not ipsilateral) hind paw and induced significant mechanical hypersensitivity, which was similar to mechanical allodynia induced by peripheral nerve injury. In contrast, microinjection of different doses of recombinant rat TGF-β1 (500, 250, 100ng) into the RN contralateral to the nerve injury side of SNI rats dose-dependently increased the paw withdrawal threshold and significantly alleviated mechanical allodynia induced by SNI. These results suggest that TGF-β in the RN participates in nociceptive processing and plays antinociceptive effects under normal physiological condition and in the development of neuropathic pain induced by SNI.
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