RESUMEN

The ventrolateral periaqueductal gray matter (vlPAG) plays a critical role in the pathogenesis of migraine and few studies have shown that vlPAG might be involved in the pathophysiology of epilepsy. But its roles in epileptogenesis and comorbid relationship between migraine and epilepsy have never been reported. In this study, the impairments of vlPAG neuronal network during spontaneous recurrent seizure (SRS) development after status epilepticus (SE) were investigated, and the pain sensitivity as well as the SRS investigated after neurochemical lesion to vlPAG to determine the role of vlPAG in epileptogenesis and in migraine comorbidity with epilepsy. Neuronal loss and alterations of excitatory and inhibitory neural transmission within vlPAG accompanied the development of epileptogenesis induced by SE. On the other hand, neurochemical lesion to vlPAG enhanced frequency and duration of spontaneous seizure event and frequency of epileptiform inter-ictal spike discharges in electroencephalography (EEG), but decreased pain threshold in epileptic rats. This indicates an involvement of the pain regulating structure, vlPAG, in the pathogenesis of epilepsy. This may imply that vlPAG network alterations could be a possible underlying mechanism of the interactive comorbid relationship between epilepsy and migraine.

Asunto(s)

RESUMEN

Different types of trigeminal pains are frequently associated with psychophysiological concerns. Orexin-A and orexin 1 receptor (OX1R) are involved in modulation of both trigeminal pain and anxiety responses. Ventrolateral periaqueductal gray matter (vlPAG), a controlling site for nociception and emotion, receives orexinergic inputs. Here, the role of vlPAG OX1Rs and their interaction with cannabinoid 1 (CB1) receptor was evaluated in anxiety-like behavior following capsaicin-induced dental pulp pain. Rats were cannulated in the vlPAG and orexin-A was injected at the doses of 0.17, 0.35 and 0.51 µg/rat prior to the induction of pain. The elevated plus maze (EPM) and open field (OF) tests were used for assessing the anxiety responses. In addition, the induction of c-fos, in the vlPAG, was investigated using immunofluorescence microscopy. Capsaicin-treated rats displayed significantly higher anxiogenic behavior on EPM and OF tests. Pretreatment with orexin-A (0.51 µg/rat) attenuated capsaicin-mediated nociception, while exaggerated anxiogenic responses (p < 0.05). In addition, orexin-A effects were diminished by the administration of OX1R (SB-334867, 12 µg/rat) and cannabinoid 1 (AM251, 4 µg/rat) receptor antagonists. Intradental capsaicin induced a significant increase in c-fos expression in the vlPAG that was exaggerated by orexin-A (0.51 µg/rat). Blockage of OX1R and CB1 receptors attenuated the effect of orexin-A on c-fos expression in capsaicin-treated rats. In conclusion, the data suggest that manipulation of OX1R and CB1 receptors in the vlPAG alters capsaicin-evoked anxiety like behaviors and c-fos induction in rats.

Asunto(s)

RESUMEN

Recent work has led to a better understanding of the neural mechanisms underlying the extinction of Pavlovian fear conditioning. Long-term synaptic changes in the medial prefrontal cortex (mPFC) are critical for extinction learning, but very little is currently known about how the mPFC and other brain areas interact during extinction. The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning. Inhibitors of opioid and N-methyl-d-aspartic acid (NMDA) receptors were applied to the ventrolateral periaqueductal gray matter (vlPAG) and amygdala shortly before extinction training. Results from these experiments show that blocking opioid receptors in the vlPAG prevented the formation of extinction memory, whereas NMDA receptor blockade had no effect. Conversely, blocking NMDA receptors in the amygdala disrupted the formation of fear extinction memory, but opioid receptor blockade in the same brain area did not. Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training. Only opioid receptor blockade in the vlPAG disrupted ERK phosphorylation in the mPFC and amygdala. These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.