Activation of extracellular signal-regulated kinase in the trigeminal ganglion following both treatment of the dura mater with capsaicin and cortical spreading depression

The trigeminal ganglion (TG) refers to sensory neurons bodies that innervate the spinal cord and peripheral axons that innervate teeth. The tetrodotoxin-sensitive sodium (NA) channels (Nav1.7) play important roles in the pathophysiology of pain. In this study, we investigated the TG expression of Nav1.7 and extracellular signal-regulated kinase (ERK) in a rat model of pulpitis to explore the correlation between these channels and inflammatory pain. Pulpitis was confirmed by hematoxylin-eosin staining. In this study, we demonstrated that the reflex of rats to mechanical stimulation increases after pulp exposure and that the exposed rat molar pulp can upregulate the expression of Nav1.7 and ERK in the rat TG. Three days after rat pulp exposure, the expression levels of the two ion channels in the TG increased. TG target injection of PF04856264, a Nav1.7 inhibitor, dose-dependently increased the mechanical pain threshold and was able to inhibit ERK expression. TG target injection of PD98059, an ERK inhibitor, dose-dependently increased the mechanical pain threshold. These factors simultaneously resulted in the highest production. In this study, with the established link to inflammatory pain, we found that Nav1.7 and ERK both play important roles in the induction of inflammatory pain caused by pulpitis. We also found a correlation between the expression levels of Nav1.7 and ERK and the degree of inflammatory pain. Furthermore, ERK signaling pathways were promoted by the Nav1.7 in TG after pulpitis.

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Selective cephalic upregulation of p-ERK, CamKII and p-CREB in response to glyceryl trinitrate infusion

Cephalalgia ◽

10.1177/0333102417722511 ◽

2017 ◽

Vol 38 (6) ◽

pp. 1057-1070 ◽

Cited By ~ 1

Author(s):

Roshni Ramachandran ◽

Sara Hougaard Pedersen ◽

Dipak Vasantrao Amrutkar ◽

Steffen Petersen ◽

Julie Mie Jacobsen ◽

...

Keyword(s):

Spinal Cord ◽

Dorsal Root Ganglion ◽

Dorsal Horn ◽

Trigeminal Ganglion ◽

Dura Mater ◽

Dorsal Root ◽

Spinal Cord Dorsal Horn ◽

Thoracic Spinal Cord ◽

Thoracic Spinal ◽

Extracellular Signal

Background A common characteristic of migraine-inducing substances is that they cause headache and no pain in other areas of the body. Few studies have compared pain mechanisms in the trigeminal and spinal systems and, so far, no major differences have been noted. We compared signalling molecules in the trigeminal and spinothalamic system after infusion of the migraine-provoking substance glyceryltrinitrate. Method A catheter was placed in the femoral vein of rats and one week later glyceryltrinitrate 4 µg/kg/min was infused for 20 min. Protein expression in the dura mater, trigeminal ganglion, nucleus caudalis, dorsal root ganglion and the dorsal horn of the thoracic spinal cord was analysed at different time points using western blotting and immunohistochemistry. Results Glyceryltrinitrate caused a threefold increase in expression of phosphorylated extracellular signal-regulated kinases at 30 min in the dura mater and nucleus caudalis ( P < 0.05) and at 2 h in the trigeminal ganglion with very few expressions in the dorsal root ganglion. In the nucleus caudalis, expression of phosphorylated extracellular signal-regulated kinases and Cam KII increased 2.6-fold and 3.2-fold, respectively, at 2 h after glycerytrinitrate infusion ( P < 0.01). p-CREB/ATF-1 upregulation was observed only at 30 min ( P < 0.05) in the nucleus caudalis. None of these markers showed increased expression in the regions of thoracic spinal cord dorsal horn. Conclusion The dura, trigeminal ganglion and nucleus caudalis are activated shortly after glycerytrinitrate infusion with long-lasting expression of phosphorylated extracellular signal-regulated kinases observed in the nucleus caudalis. These activations were not observed at the spinal level.

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Does Metoprolol Inhibit the Cortical Spreading Depression? Acute Effects of Systematic Metropol on CSD in Rats

Cephalalgia ◽

10.1111/j.1468-2982.2007.01390.x ◽

2007 ◽

Vol 27 (9) ◽

pp. 1010-1013 ◽

Cited By ~ 7

Author(s):

M Alemdar ◽

Ö Akman ◽

HM Selekler ◽

SŞ Komsuoğlu ◽

N Ateş

Keyword(s):

Dura Mater ◽

Cortical Spreading Depression ◽

Wistar Rats ◽

Spreading Depression ◽

Migraine Prophylaxis ◽

Migraine Aura ◽

Direct Effects ◽

Acute Effects ◽

Before And After ◽

Induction Model

Cortical spreading depression (CSD) is supposed to be the underlying biological basis of the migraine aura. Metoprolol was proven to be effective in migraine prophylaxis in clinical trials, but its mechanism of action has not been clarified yet. We studied direct effects of metoprolol on a continuous CSD induction model in rats. Six adult Wistar rats were anaesthetized with intraperitoneal thiopental (50 mg/kg). CSD was induced with application of 1 M KCL through a burr hole into the left frontal dura-mater, and recorded by an Ag/AgCl DC electrode on the left parietal dura-mater. After a basal recording of CSD induction during the first 40-min period, metoprolol (5 mg/kg) was infused within 4 min. Then DC recordings were maintained for a further 120 min. Any significant differences in total number and duration of CSDs before and after metoprolol administration were not detected. This study suggests that the mode of action of metoprolol in prophylaxis is not via direct CSD inhibition.

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A potential role for two brainstem nuclei in craniovascular nociception and the triggering of migraine headache

Cephalalgia ◽

10.1177/0333102420960039 ◽

2020 ◽

pp. 033310242096003

Author(s):

Alessandro S Zagami ◽

Sumaiya Shaikh ◽

David Mahns ◽

Geoffrey A Lambert

Keyword(s):

Dura Mater ◽

Cortical Spreading Depression ◽

Migraine Headache ◽

Spreading Depression ◽

Light Flash ◽

Discharge Rate ◽

Indirect Evidence ◽

Second Order ◽

Facial Skin ◽

Migraine Triggers

Aim To use an animal model of migraine to test whether migraine headache might arise from a brainstem-trigeminal nucleus pathway. Methods We measured evoked and spontaneous activity of second-order trigeminovascular neurons in rats to test whether the activity of these neurons increased following the induction of cortical spreading depression or the imposition of light flash – two potential migraine triggers, or headache provokers. We then tested whether drugs that could activate, or inactivate, neurons of the nucleus raphe magnus or the periaqueductal gray matter, would affect any such increases selectively for the dura mater. Results Injection of sodium glutamate (a neuronal excitant) into these two nuclei selectively inhibited the responses of trigeminovascular second-order neurons to dura mater, but not to facial skin, stimulation. Injection of lignocaine (a local anaesthetic) into these nuclei selectively potentiated the responses of these neurons to dura, but not to facial skin, stimulation. Furthermore, injections into either nucleus of glutamate inhibited the increase in the ongoing discharge rate of these neurons produced by cortical spreading depression and light flash. Conclusions These results provide indirect evidence that trigeminovascular nociception may be tightly controlled by these two nuclei, whereas cutaneous trigeminal sensation may be less so. These nuclei may be relays of one possible brainstem-trigeminal pathway that could mediate migraine headache. Modification of neuronal activity in these two nuclei produced by migraine (headache) triggers may lie behind the pain of a migraine attack, at least in some cases.

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Effect of cortical spreading depression on basal and evoked traffic in the trigeminovascular sensory system

Cephalalgia ◽

10.1177/0333102411422383 ◽

2011 ◽

Vol 31 (14) ◽

pp. 1439-1451 ◽

Cited By ~ 50

Author(s):

Geoffrey A Lambert ◽

Linda Truong ◽

Alessandro S Zagami

Keyword(s):

Trigeminal Ganglion ◽

Cortical Spreading Depression ◽

Spreading Depression ◽

Discharge Rate ◽

Sensory System ◽

Subsequent Development ◽

Sensory Stimulation ◽

Spontaneous Discharge ◽

Facial Skin ◽

Discharge Rates

Aim: To use an animal model to test whether migraine pain arises peripherally or centrally. Methods: We monitored the spontaneous and evoked activity of second-order trigeminovascular neurons in rats to test whether traffic increased following a potential migraine trigger (cortical spreading depression, CSD) and by what mechanism any such change was mediated. Results: Neurons ( n = 33) responded to stimulation of the dura mater and facial skin with A-δ latencies. They were spontaneously active with a discharge rate of 6.1 ± 6.4 discharges s−1. Injection of 10 µg lignocaine into the trigeminal ganglion produced a fully reversible reduction of the spontaneous discharge rate of neurons. Neuronal discharge rate returned to normal by 90 min. Lignocaine reduced the evoked responses of neurons to dural stimulation to 37% and to facial skin stimulation to 53% of control. Induction of CSD by cortical injection of KCl increased the spontaneous discharge rate of neurons from 2.9 to 16.3 discharges s−1 at 20 min post CSD. Injection of 10 µg lignocaine into the trigeminal ganglion at this time failed to arrest or reverse this increase. Injection of lignocaine prior to the initiation of CSD failed to prevent the subsequent development of CSD-induced increases in discharge rates. Conclusions: These results suggest that there is a continuous baseline traffic in primary trigeminovascular fibres and that CSD does not act to increase this traffic by a peripheral action alone − rather, it must produce some of its effect by a mechanism intrinsic to the central nervous system. Thus the pain of migraine may not always be the result of peripheral sensory stimulation, but may also arise by a central mechanism.

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