The Involvement of DDAH1 in the Activation of Spinal NOS Signaling in Early Stage of Mechanical Allodynia Induced by Exposure to Ischemic Stress in Mice

Abstract

The pathophysiological mechanism of central post-stroke pain (CPSP) is complicated and not well understood. Recently, it has been reported that an increase in the levels of spinal nitric oxide synthetase (NOS) occurs in cerebral ischemia, and spinal NOS is involved in the development of neuropathic pain. The aim of this study was to elucidate the mechanism of spinal NOS signaling in the development of CPSP. Male ddY mice were subjected to 30-min long bilateral carotid artery occlusion (BCAO). The withdrawal responses to mechanical stimuli were significantly increased as determined with von Frey test on days 1 and 3 after BCAO. Protein expression of spinal N (G) ,N (G)-dimethylarginine dimethylaminohydralase 1 (DDAH1), a key enzyme involved in the metabolism of the endogenous NOS, increased on day 1 after BCAO, but not on day 3. Intrathecal (i.t.) injection of PD404182, a DDAH1 inhibitor, significantly suppressed mechanical allodynia on day 1, but not on day 3 after BCAO. In addition, i.t. administration of N G-nitro-L-arginine methyl ester (L-NAME), a non-selective NOS inhibitor, significantly blocked mechanical allodynia on days 1 and 3 after BCAO. Furthermore, BCAO-induced increment of spinal NOS activity was inhibited by the pretreatment with PD404182. These results suggest that mechanical allodynia in the early stage of CPSP is caused by increment of NOS activity through upregulated DDAH1 in the spinal cord.

Secondary damage and neuroinflammation in the spinal dorsal horn mediate post-thalamic hemorrhagic stroke pain hypersensitivity: SDF1-CXCR4 signaling mediation

“…One possibility is that primary thalamic damage can cause retrograde axonal degeneration of the STT projecting fiber terminals, resulting in secondary spinal STT neuronal cell body death and neuroinflammation. Some previous reports support our presumption: (1) diffuse tensor tractography (DTT) showed likely damage of STT fibers after CPSP (Jang et al, 2019;Park et al, 2021); (2) involvement of spinal NOS signal in the development of bilateral carotid artery occlusion induced CPSP (Matsuura et al, 2019); (3) blockade of peripheral sensory input resulted in amelioration of CPSP (Haroutounian et al, 2018;Choi et al, 2021b). To address the above question, this study was designed to examine whether secondary neuronal death and neuroinflammation occur in the spinal dorsal horn after an establishment of the THS-induced pain hypersensitivity in rats, and if any, whether i.t.…”

Role of Sensory Pathway Injury in Central Post-Stroke Pain: A Narrative Review of Its Pathogenetic Mechanism

“… 18 Increased expression of spinal HMGB1 and the enzyme protein N(G), N(G)-Dimethylarginine dimethylaminohydrolase 1 (DDAH1), which regulates NOS signaling, in a post-ischemic stroke pain model resulted in bilateral carotid artery occlusion (BCAO). 17 , 19 HMGB1 is a non-histone nuclear protein that plays a critical role in regulating gene transcription. It can aggravate inflammation and pain via the TLR4 or RAGE signaling pathways.…”

“…Elevated DDAH1 may be involved in CPSP occurrence by enhancing NO signaling. 19 A proteomic study of the spinal cord and DRG of mice with BCAO revealed that DDAH1 was involved and that its levels were altered, suggesting the role of NOS signaling in the inflammatory response at spinal cord after a stroke. 20 Anterograde, retrograde, and trans-synaptic degeneration may occur after nerve fiber injury.…”