Abstract by Jacob Edvinsson

Migraine headache affects approximately 15% of the global population according to epidemiological studies conducted by the World Health Organization (WHO). Many believe that this painful affliction originates in the vasodilation of cranial vasculature. A view that has been challenged to the point that most headache researchers now adhere to the hypothesis of migraine pain as a neuronal disorder. This shift in paradigm is due to evidence of migraine attacks initiated by drugs lacking vasodilatory capabilities. Evidence supporting the neurological hypothesis include new pharmacological treatments effective in treating migraine attacks (e.g. ditans, gepants and monoclonal antibodies).

The work presented in this thesis addresses some of the most migraine-implicated neuropeptides and their receptors. In particular, the calcitonin gene-related peptide (CGRP) and it's receptor is thoroughly implicated in migraine pathophysiology through the efficacy of CGRP receptor antagonists and monoclonal antibodies. Pituitary adenylate cyclase-activating peptide 38 (PACAP-38), Substance P (SP), 5-Hydroxytryptamine (5-HT), and their respective receptors were investigated due to their implication in headache pathology.

In study I, we observed the alignment of CGRP immunoreactive C-fibre boutons with the node of Ranvier on CGRP receptor immunoreactive Aδ-fibres. Furthermore, we demonstrated the stimulated release of CGRP from non-terminal C-fibre axons within the trigeminal system. Based on this study we generated the hypothesis that modulatory crosstalk can occur between fibre types in the peripheral nervous system via the extrasynaptic release of neuropeptides. Lastly, we suggested the node of Ranvier as a plausible target for CGRP receptor targeting drugs.

In study II, PACAP was not observed to be released from C-fibres in the dura mater, however PACAP could be released from trigeminal ganglion samples. This release is likely limited to come from neuron somas or PACAP-27, which was not the focus of the study. PACAP-38 immunoreactivity was detected in neuron somas, but not in C-fibres, and the PAC₁ receptor was mainly observed in satellite glial cells. Taken together, this study argues that PACAP-38 and the PAC₁ receptor are unlikely targets for alleviating migraine pain.

In study III, SP was observed to co-localize with CGRP in C-fibre boutons that could be found to align with the node of Ranvier as seen in study I. We observed a minor stimulated release of SP, mirroring the immunohistochemical expression. Based on this, we propose that SP and CGRP signalling may work in tandem to exacerbate headache pain.

In study IV, 5-HT was detected in a subpopulation of C-fibres not expressing CGRP or SP. The associated neurons of these fibres are likely located within the brainstem. In agreement with this, stimulated 5-HT release was only observed in the same region as this C-fibre subpopulation. Furthermore, 5-HT_1B/D receptors are abundantly expressed within the trigeminal ganglion, while the 5-HT_1F receptor is only faintly present. Here, we demonstrate that the inhibitory effect of Lasmiditan on the stimulated release of CGRP in the trigeminal system is in part mediated by 5-HT_1B/1D receptors.

In conclusion, I believe these studies hold relevancy to the understanding of pain signalling in headache pathophysiology.