Abstract
Orofacial pain and headache disorders are among the most debilitating pain conditions. While the pathophysiological basis of these disorders may be diverse, it is generally accepted that a common mechanism behind the arising pain is the sensitization of extra- and intracranial trigeminal primary afferents. In the present study we investigated gene expression changes in the trigeminal ganglia (TRG), trigeminal nucleus caudalis (TNC) and peripheral blood mononuclear cells (PBMC) evoked by Complete Freund's Adjuvant (CFA)-induced orofacial inflammation in rats, as a model of trigeminal sensitization. Microarray analysis revealed 512 differentially expressed genes between the ipsi- and contralateral TRG samples 7 days after CFA injection. Time-dependent expression changes of G-protein coupled receptor 39 (Gpr39), kisspeptin-1 receptor (Kiss1r), kisspeptin (Kiss1), as well as synaptic plasticity-associated Lkaaear1 (Lkr) and Neurod2 mRNA were described on the basis of qPCR results. The greatest alterations were observed on day 3 ipsilaterally, when orofacial mechanical allodynia reached its maximum. This corresponded well with patterns of neuronal (Fosb), microglia (Iba1), and astrocyte (Gfap) activation markers in both TRG and TNC, and interestingly also in PBMCs. This is the first description of up- and downregulated genes both in primary and secondary sensory neurones of the trigeminovascular system that might play important roles in neuroinflammatory activation mechanisms. We are the first to show transcriptomic alterations in the PBMCs that are similar to the neuronal changes. These results open new perspectives and initiate further investigations in the research of trigeminal pain disorders.
Highlights
Orofacial pain and headache disorders are among the most debilitating pain conditions
The aim of the present study was to follow the temporal changes of facial mechanonociceptive thresholds and gene expression in trigeminal ganglion (TRG), trigeminal nucleus caudalis (TNC) neurones and peripheral blood mononuclear cells (PBMC) after Complete Freund’s Adjuvant (CFA) inflammation using microarray and qPCR analyses in order to get a better insight into the mechanisms of trigeminal pain disorders
We described up- and downregulation of distinct genes that are likely to be involved in the activation and sensitization of primary and secondary trigeminal neurons
Summary
Orofacial pain and headache disorders are among the most debilitating pain conditions. While the pathophysiological basis of these disorders may be diverse, it is generally accepted that a common mechanism behind the arising pain is the sensitization of extra- and intracranial trigeminal primary afferents. It has been described that there is convergence of extra- and intracranial primary afferents in the TNC (Burstein et al, 1998). Sensitization of these secondary nociceptive neurons might be responsible for the phenomenon of the facial allodynia developing in primary headaches (Burstein et al, 2000). A similar mechanism could induce the headache associated with disorders of extracranial structures. Inflammation of the temporal artery, temporomandibular joint, sinuses or orbit can induce headache which could have the same characteristics as the primary disorders. Co-morbidity of migraine and temporomandibular disorders has been reported (Romero-Reyes and Uyanik, 2014)
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