Abstract
Thalamic pain, a type of central poststroke pain, frequently occurs following ischemia/hemorrhage in the thalamus. Current treatment of this disorder is often ineffective, at least in part due to largely unknown mechanisms that underlie thalamic pain genesis. Here, we report that hemorrhage caused by microinjection of type IV collagenase or autologous whole blood into unilateral ventral posterior lateral nucleus and ventral posterior medial nucleus of the thalamus increased the expression of Fgr, a member of the Src family nonreceptor tyrosine kinases, at both mRNA and protein levels in thalamic microglia. Pharmacological inhibition or genetic knockdown of thalamic Fgr attenuated the hemorrhage-induced thalamic injury on the ipsilateral side and the development and maintenance of mechanical, heat, and cold pain hypersensitivities on the contralateral side. Mechanistically, the increased Fgr participated in hemorrhage-induced microglial activation and subsequent production of TNF-α likely through activation of both NF-κB and ERK1/2 pathways in thalamic microglia. Our findings suggest that Fgr is a key player in thalamic pain and a potential target for the therapeutic management of this disorder.
Highlights
Central poststroke pain (CPSP), a chronic neuropathic pain syndrome, is often induced by damage and/or dysfunction of the central nervous system following stroke
To demonstrate the role of Fgr in hemorrhage-induced thalamic pain, we first examined the expression of Fgr in the thalamus after microinjection of Coll IV into thalamic ventral posterior medial nucleus (VPM) and ventral posterior lateral nucleus (VPL) in mice, a preclinical animal model that mimics hemorrhage-induced thalamic pain in clinic cases [16]
A double labeling assay showed that the majority of Fgr-labeled immunoreactivities overlapped with immunoreactivities labeled by ionized calcium-binding adapter molecule 1 (Iba1) and few with immunoreactivities labeled by glial fibrillary acidic protein (GFAP), CD68, or NeuN in thalamic cells 7 days after Coll IV microinjection (Figure 1K and Supplemental Figure 3)
Summary
Central poststroke pain (CPSP), a chronic neuropathic pain syndrome, is often induced by damage and/or dysfunction of the central nervous system following stroke. Patients with CPSP commonly experience long-term hyperalgesia, allodynia, spontaneous pain, and other sensory deficits, in some cases for the rest of their lives. These pain hypersensitivities impair the patients’ daily activities, undermining their quality of life and rehabilitation process [2, 3]. Persistent CPSP and associated dysfunction (e.g., loss of sleep, social interaction, and ability to work) lead to further mental health disorders, in particular depression and anxiety [4]. Understanding the mechanisms underlying CPSP may open a new avenue for therapeutic management of this disorder
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