Is there an Influence of Autonomic Nerves on Sensory Nerves in the Meninges? – Release of CGRP and PGE2 in vitro

The perivascular fibers in the dura mater are a putative source of headache. They are either efferent sympathetic or parasympathetic or afferent in the trigeminovascular system. Because the fibers join each other densely, one system might influence the other systems by neurotransmitter or peptide release. It is generally accepted that the trigeminovascular system is activated during headache, e.g., migraine. The release of the vasodilatory neuropeptide CGRP is an indicator for nociceptor activation and neurogenic inflammation which accompanies the headache. The release of PGE₂ supports the inflammatory process. Here we investigated in an in vitro release model of the dura whether transmitters of sympathetic and parasympathetic fibers may influence the release of CGRP and PGE₂ from afferent fibers. Rats were decapitated and the skull was divided in halves. The cavities lined with dura were repetitively filled with different sample solutions. The CGRP and PGE₂ content of the samples was measured with an enzyme immunoassay. Carbachol (10^–4 M) neither influenced the basal release of CGRP nor that of PGE₂. However, a reduction of the release stimulated by a mixture of inflammatory mediators could be observed suggesting that parasympathetic fibers might influence primary afferents during activation. No significant influences on the release of CGRP were seen with norepinephrine (NE, 10^–4 M). In addition, NE had no influence on the stimulated release of PGE₂. However, basal release of PGE₂ was massively enhanced by NE, an effect which outlasted application. When serotonin was added to NE this effect was reduced by half. The reduction was probably due to 5-HT1D receptors. NE had no influence on the release of CGRP from primary afferent neurons showing that NE does not directly activate or influence afferent fibers. However, the basal level of PGE₂ was increased massively by NE, a process probably controlled by 5-HT1D receptors. The balance between 5-HT and NE, both stored in sympathetic fibers, might be a crucial mechanism in the control of PGE₂ levels in the meninges.