Contributions of p38 and ERK to the antinociceptive effects of TGF-β1 in chronic constriction injury-induced neuropathic rats

Transforming growth factor-βs (TGF-βs) are a group of multifunctional proteins that have neuroprotective roles in various experimental models. We previously reported that intrathecal (i.t.) injections of TGF-β1 significantly inhibit neuropathy-induced thermal hyperalgesia, spinal microglia and astrocyte activation, as well as upregulation of tumor necrosis factor-α. However, additional cellular mechanisms for the antinociceptive effects of TGF-β1, such as the mitogen-activated protein kinase (MAPK) pathway, have not been elucidated. During persistent pain, activation of MAPKs, especially p38 and extracellular signal-regulated kinase (ERK), have crucial roles in the induction and maintenance of pain hypersensitivity, via both nontranscriptional and transcriptional regulation. In the present study, we used a chronic constriction injury (CCI) rat model to explore the role of spinal p38 and ERK in the analgesic effects of TGF-β1.

The present results demonstrate that suppressing p38 and ERK activity affects TGF-β1-induced analgesia during neuropathy.

We investigated the cellular mechanisms of the antinociceptive effects of i.t. injections of TGF-β1 in CCI induced neuropathic rats by spinal immunohistofluorescence analyses.

The results demonstrated that the antinociceptive effects of TGF-β1 (5 ng) were maintained at greater than 50 % of the maximum possible effect in rats with CCI for at least 6 h after a single i.t. administration. Thus, we further examined these alterations in spinal p38 and ERK from 0.5 to 6 h after i.t. administration of TGF-β1. TGF-β1 significantly attenuated CCI-induced upregulation of phosphorylated p38 (phospho-p38) and phosphorylated ERK (phospho-ERK) expression in the dorsal horn of the lumbar spinal cord. Double immunofluorescence staining illustrated that upregulation of spinal phospho-p38 was localized to neurons, activated microglial cells, and activated astrocytes in rats with CCI. Additionally, increased phospho-ERK occurred in activated microglial cells and activated astrocytes. Furthermore, i.t. administration of TGF-β1 markedly inhibited phospho-p38 upregulation in neurons, microglial cells, and astrocytes. However, i.t. injection of TGF-β1 also reduced phospho-ERK upregulation in microglial cells and astrocytes. Conclusions: The present results demonstrate that suppressing p38 and ERK activity affects TGF-β1-induced analgesia during neuropathy.