Abstract
Pain is one of the most severe concerns in tongue cancer patients. However, the underlying mechanisms of tongue cancer pain are not fully understood. We investigated the molecular mechanisms of tongue cancer-induced mechanical allodynia in the tongue by squamous cell carcinoma (SCC) inoculation in rats. The head-withdrawal threshold of mechanical stimulation (MHWT) to the tongue was reduced following SCC inoculation, which was inhibited by intracisternal administration of 10Panx, an inhibitory peptide for pannexin 1 (PANX1) channels. Immunohistochemical analyses revealed that the expression of PANX1 was upregulated in the trigeminal spinal subnucleus caudalis (Vc) following SCC inoculation. The majority of PANX1 immunofluorescence was merged with ionized calcium-binding adapter molecule 1 (Iba1) fluorescence and a part of it was merged with glial fibrillary acidic protein (GFAP) fluorescence. Spike frequencies of Vc nociceptive neurons to noxious mechanical stimulation were significantly enhanced in SCC-inoculated rats, which was suppressed by intracisternal 10Panx administration. Phosphorylated extracellular signal-regulated kinase (pERK)-immunoreactive (IR) neurons increased significantly in the Vc after SCC inoculation, which was inhibited by intracisternal 10Panx administration. SCC inoculation-induced MHWT reduction and increased pERK-IR Vc neuron numbers were inhibited by P2X7 purinoceptor (P2X7R) antagonism. Conversely, these effects were observed in the presence of P2X7R agonist in SCC-inoculated rats with PANX1 inhibition. SCC inoculation-induced MHWT reduction was significantly recovered by intracisternal interleukin-1 receptor antagonist administration. These observations suggest that SCC inoculation causes PANX1 upregulation in Vc microglia and adenosine triphosphate released through PANX1 sensitizes nociceptive neurons in the Vc, resulting in tongue cancer pain.
Highlights
Squamous cell carcinoma (SCC) is one of the most common cancers in the intraoral structures, oral mucosa and tongue and it destroys the intraoral mucosa, gingiva and tongue tissues with its invasion [1]
pannexin 1 (PANX1) Is Involved in the Development of Mechanical Allodynia in the Tongue following SCC Inoculation
The present results are summarized as follows: (1) Mechanical hypersensitivity was induced in the tongue of SCC-inoculated rats; (2) Intracisternal administration of 10Panx inhibited the development of SCC inoculation-induced mechanical allodynia in the tongue; (3) Increased neuronal activity and the number of Phosphorylated extracellular signal-regulated kinase (pERK)-IR Vc neurons following SCC inoculation were suppressed by i.c. 10Panx; (4) Intracistrenal administration of Brilliant Blue G (BBG) inhibited SCC-induced reduction of mechanical head-withdrawal threshold (MHWT) and an increase in the number of pERK-IR neurons in the Vc; (5) Intracisternal administration of BzATP caused a reduction in MHWT and an increase in the number of pERK-IR Vc neurons in 10Panx-administered SCC rats; and (6) Reduced MHWT was recovered by i.c
Summary
Squamous cell carcinoma (SCC) is one of the most common cancers in the intraoral structures, oral mucosa and tongue and it destroys the intraoral mucosa, gingiva and tongue tissues with its invasion [1]. SCC growth in the oral cavity causes tissue destruction and damage to the trigeminal nerve and local inflammation in the oral structures during tumor growth causes a deficit in oral functions, such as chewing and swallowing [2]. Studies have shown that trigeminal nerve injury caused by the tumor leads to persistent neuropathic pain in a broad area of the orofacial regions [3]. SCC in the tongue causes several changes in TG neurons and in the trigeminal spinal subnucleus caudalis (Vc), where it activates microglia [6]. The changes in the central nervous system (CNS) caused by cancer are progressively evident, CNS changes caused by SCC are not fully understood
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