Abstract
A large percentage of primary sensory neurons in the trigeminal ganglia (TG) contain neuropeptides such as tachykinins or calcitonin gene-related peptide. Neuropeptides released from the central terminals of primary afferents sensitize the secondary nociceptive neurons in the trigeminal nucleus caudalis (TNC), but also activate glial cells contributing to neuroinflammation and consequent sensitization in chronic orofacial pain and migraine. In the present study, we investigated the newest member of the tachykinin family, hemokinin-1 (HK-1) encoded by the Tac4 gene in the trigeminal system. HK-1 had been shown to participate in inflammation and hyperalgesia in various models, but its role has not been investigated in orofacial pain or headache. In the complete Freund’s adjuvant (CFA)-induced inflammatory orofacial pain model, we showed that Tac4 expression increased in the TG in response to inflammation. Duration-dependent Tac4 upregulation was associated with the extent of the facial allodynia. Tac4 was detected in both TG neurons and satellite glial cells (SGC) by the ultrasensitive RNAscope in situ hybridization. We also compared gene expression changes of selected neuronal and glial sensitization and neuroinflammation markers between wild-type and Tac4-deficient (Tac4-/-) mice. Expression of the SGC/astrocyte marker in the TG and TNC was significantly lower in intact and saline/CFA-treated Tac4-/- mice. The procedural stress-related increase of the SGC/astrocyte marker was also strongly attenuated in Tac4-/- mice. Analysis of TG samples with a mouse neuroinflammation panel of 770 genes revealed that regulation of microglia and cytotoxic cell-related genes were significantly different in saline-treated Tac4-/- mice compared to their wild-types. It is concluded that HK-1 may participate in neuron-glia interactions both under physiological and inflammatory conditions and mediate pain in the trigeminal system.
Highlights
Sensitization of trigeminal nociceptors by inflammatory mediators is a major factor of orofacial pain and headache disorders by causing hyperalgesia and allodynia
The cell bodies of the primary sensory neurons are located in the trigeminal ganglia (TG) and their central terminals relay the protopathic information to the spinal trigeminal nucleus caudalis (TNC) and the upper cervical dorsal horn
Mithogrelioavl ecre,llwaecthivaivtye ianlsbootphrothveidTeGd aenvdidtehneceTNonCa. possible physiological role of HK-1 in the trigeminal system by showing that there is a baseline difference in the expression of genes associated with glial cell activity in both the TG and the Previous studies by our and other groups have established that HK-1 contributes to the development of hyperalgesia in both acute and chronic pain models
Summary
Sensitization of trigeminal nociceptors by inflammatory mediators is a major factor of orofacial pain and headache disorders by causing hyperalgesia and allodynia. Tachykinins can be released both from the peripheral and central endings of primary sensory neurons contributing to inflammatory processes and pain transmission [9,10]. NK-1 receptor antagonists were shown to effectively reduce neuropathic mechanical hyperalgesia and inflammatory pain in animal models [13,14,15]. SP released from the peripheral terminals of trigeminal neurons induces plasma protein extravasation and vasodilatation in the dura mater [16], while centrally in the TNC it contributes to pain transmission [17,18]. CFA-Induced Orofacial Inflammation Upregulates Tac mRNA in Both Primary Sensory Neurons and SG2.C3s. CofFtAhe-IMndouucseedTOGrofacial Inflammation Upregulates Tac mRNA In Both Primary Sensory Neurons and SGCs of the Mouse TG to Tac expression found in rat TG, basal Tac mRNA was detected both in sensory neuronSsimanildarSlyGCtosToafct4heexmproeussseioTnGfo(uFingdurine 3raa,t lTeGft,pbaanseall).TAacl4som, mRNouAsewTaasc4dmeteRcNteAd wboatshsihnoswennstoory benueuprroengus laanteddSiGnCressopfotnhsee mtooCuFsAe -TiGnd(uFcigedurienfl3aa,mlemftaptiaonne(lF).igAulsreo,3ma,oruigshetTpaacn4eml)R.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
