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

Abstract

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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.

• Authors: Nan-Fu Chen, Wu-Fu Chen, Chun-Sung Sung, Ching-Hsiang Lu, Chun-Lin Chen, Han-Chun Hung, Chien-Wei Feng, Chun-Hong Chen, Kuan-Hao Tsui, Hsiao-Mei Kuo, Hui-Min David Wang, Zhi-Hong Wen, Shi-Ying Huang
• Journal: The journal of headache and pain (J Headache Pain) Vol. 17 Issue 1 Pg. 72 (Dec 2016) ISSN: 1129-2377 [Electronic] England
• PMID: 27541934 (Publication Type: Journal Article)

Chemical References

• Receptors, Transforming Growth Factor beta
• Protein Serine-Threonine Kinases
• Extracellular Signal-Regulated MAP Kinases
• p38 Mitogen-Activated Protein Kinases
• Receptor, Transforming Growth Factor-beta Type I
• Tgfbr1 protein, rat

Topics

• Animals
• Constriction, Pathologic (pathology)
• Disease Models, Animal
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Inflammation (pathology)
• Male
• Peripheral Nerve Injuries (pathology)
• Protein Serine-Threonine Kinases (pharmacology)
• Rats
• Rats, Wistar
• Receptor, Transforming Growth Factor-beta Type I
• Receptors, Transforming Growth Factor beta (antagonists & inhibitors)
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases (metabolism)