Abstract
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) participates in the regulation of cellular stress and inflammatory responses, but its function in neuropathic pain remains poorly understood. This study evaluated the role of RIPK1 in neuropathic pain following inferior alveolar nerve injury. We developed a model using malpositioned dental implants in male Sprague Dawley rats. This model resulted in significant mechanical allodynia and upregulated RIPK1 expression in the trigeminal subnucleus caudalis (TSC). The intracisternal administration of Necrosatin-1 (Nec-1), an RIPK1 inhibitor, blocked the mechanical allodynia produced by inferior alveolar nerve injury The intracisternal administration of recombinant rat tumor necrosis factor-α (rrTNF-α) protein in naive rats produced mechanical allodynia and upregulated RIPK1 expression in the TSC. Moreover, an intracisternal pretreatment with Nec-1 inhibited the mechanical allodynia produced by rrTNF-α protein. Nerve injury caused elevated TNF-α concentration in the TSC and a TNF-α block had anti-allodynic effects, thereby attenuating RIPK1 expression in the TSC. Finally, double immunofluorescence analyses revealed the colocalization of TNF receptor and RIPK1 with astrocytes. Hence, we have identified that astroglial RIPK1, activated by the TNF-α pathway, is a central driver of neuropathic pain and that the TNF-α-mediated RIPK1 pathway is a potential therapeutic target for reducing neuropathic pain following nerve injury.
Highlights
Academic Editor: Yoshizo MatsukaThe characterization of neuropathic pain is continuous and/or paroxysmal pain associated with dysesthesia or allodynia
To investigate participation of the Receptor-interacting serine/threonine protein kinase 1 (RIPK1) pathway in this recombinant rat tumor necrosis factor-α (rrTNF-α)-protein-induced mechanical allodynia, the possible participation of the RIPK1 pathway in this rrTNF-α-protein-induced mechanwe evaluated these effects following an intracisternal pretreatment with Nec-1 at 4 h before ical allodynia, we evaluated these effects following an intracisternal pretreatment with the protein injection in naïve rats.inWhereas administration
Our present study first demonstrated that Tumor necrosis factor (TNF)-α-mediated activation of RIPK1 pathway in astrocytes contributes to the development of trigeminal neuropathic pain
Summary
The characterization of neuropathic pain is continuous and/or paroxysmal pain associated with dysesthesia or allodynia. Drug development for treating neuropathic pain often focuses on the inhibition or relief of certain underlying causes or symptoms. Previous reports have demonstrated the association of RIPK1 found with several disorders, such as inflammatory disease, ischemic injury, axonal degeneration, autoimmune disease, and different cancers [5]. Recent evidence supports the involvement of RIPK1 in the processes underlying nociceptive information. A blockade of RIPK1 expression alleviates hyperalgesia and mechanical allodynia in rats with sciatic nerve injury [9]. RIPK1 has generated interest as a potential target for neuropathic pain treatment. Its function in trigeminal neuropathic pain remains unknown, with previous findings suggesting that it can modulate pain processing after various types of nerve injury
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