Abstract
The neuromodulator calcitonin gene-related peptide (CGRP) is known to facilitate nociceptive transmission in the superficial laminae of the spinal trigeminal nucleus caudalis (Sp5C). The central effects of CGRP in the Sp5C are very likely to contribute to the activation of central nociceptive pathways leading to attacks of severe headaches like migraine. To examine the potential impacts of CGRP on laminae I/II neurons at cellular and synaptic levels, we performed whole-cell patch-clamp recordings in juvenile mouse brainstem slices. First, we tested the effect of CGRP on cell excitability, focusing on neurons with tonically firing action potentials upon depolarizing current injection. CGRP (100 nM) enhanced tonic discharges together with membrane depolarization, an excitatory effect that was significantly reduced when the fast synaptic transmissions were pharmacologically blocked. However, CGRP at 500 nM was capable of exciting the functionally isolated cells, in a nifedipine-sensitive manner, indicating its direct effect on membrane intrinsic properties. In voltage-clamped cells, 100 nM CGRP effectively increased the frequency of excitatory synaptic inputs, suggesting its preferential presynaptic effect. Both CGRP-induced changes in cell excitability and synaptic drives were prevented by the CGRP receptor inhibitor BIBN 4096BS. Our data provide evidence that CGRP increases neuronal activity in Sp5C superficial laminae by dose-dependently promoting excitatory synaptic drive and directly enhancing cell intrinsic properties. We propose that the combination of such pre- and postsynaptic actions of CGRP might underlie its facilitation in nociceptive transmission in situations like migraine with elevated CGRP levels.
Highlights
Calcitonin gene-related peptide (CGRP) is produced by a considerable proportion of primary afferent neurons of the trigeminal and spinal sensory ganglia [1,2,3]
Infusion of CGRP induces headaches in patients suffering from migraine but does not cause any other pain [7,8], and CGRP receptor inhibition has been shown to be therapeutic in primary headaches like migraine [9,10]
When the membrane potential of Sp5C laminae I/II neurons was held at −70 mV, depolarizing current pulses (20–200 pA for 500 ms) elicited action potentials (APs) with characteristic discharge patterns, namely tonic, phasic and delayed spikes, or single spike (Figure 1B), consistent with previous studies [23,24,25,26]
Summary
Calcitonin gene-related peptide (CGRP) is produced by a considerable proportion of primary afferent neurons of the trigeminal and spinal sensory ganglia [1,2,3]. CGRP seems to be further enriched in trigeminal afferents that innervate intracranial structures like meninges and cerebral blood vessels [4], structures which have long been regarded as sources for the generation of headaches [5]. CGRP is important as a nociceptive mediator in the intracranial pain producing system. Infusion of CGRP induces headaches in patients suffering from migraine but does not cause any other pain [7,8], and CGRP receptor inhibition has been shown to be therapeutic in primary headaches like migraine [9,10]. Inactivation of CGRP or CGRP receptors by monoclonal antibodies promises to be extremely effective in preventing frequent migraine attacks [11]
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