Abstract
In this issue of Cephalalgia, Christensen and colleagues explore the utility of cilostazol to induce headache-like behaviours and trigeminovascular activation in rats (1) and further determine if such responses are modulated by the known anti-migraine therapeutic agent sumatriptan. The authors report that cilostazol induces headache-like behaviours in female rats including light sensitivity (photophobia) and trigeminal hyperalgesia (cephalic allodynia) combined with increased neural activation of the trigeminal nucleus caudalis (TNC). The demonstration of such headache-specific phenotypes and underlying pathophysiological mechanisms certainly suggests some promise for this novel chemically induced preclinical model; however, the lack of a predictive response to sumatriptan raises questions regarding its utility as a predictive model for translational research.
Cilostazol and migraine
Cilostazol is an inhibitor of the cAMP degrading phosphodiesterase 3 inhibitor that results in elevated intracellular cAMP levels (2). It is a potent experimental migraine-inducing agent, with up to 86% of migraineurs reporting a delayed migraine-like attack after a median of six hours (3). Of particular interest to the current study, cilostazol further induces headache-like symptoms in healthy controls (4,5) including throbbing pain and exacerbation by physical activity; however, secondary characteristics such as photo- or phonophobia are reported in ≤ 20% of subjects, suggesting photophobia was not a prominent outcome. A perceived negative outcome of the human study was the lack of therapeutic response to sumatriptan; however, it is clear that not all migraineurs respond to triptans, suggesting that an alternative triptan-resistant mechanism may be responsible. This is in agreement with clinical data on other migraine-inducing agents including nitroglycerin (NTG) that have been shown to be unresponsive to multiple therapeutic approaches (6).
It is essential to the translational nature of headache research that such migraine-inducing molecules are tested preclinically to both validate their effects and refine their use. In the current study, the authors demonstrate that the clinical effects of cilostazol are relatively well reproduced in rodents. Although no preclinical model can claim to induce migraine, it is reasonable to assume headache- or migraine-like symptoms based on careful behavioural phenotyping. Similarly, these behavioural responses (delayed light sensitivity and trigeminal hyperalgesia) were non-responsive to sumatriptan. The advantage of basic bench research is that the unanswered question above of an alternate triptan-resistant mechanism can now be tested in-vivo with a view to translating any identified mechanisms back to clinical studies.
Cilostazol vs. NTG-induced preclinical models
The most utilised preclinical induction model remains that of NTG, based on its proven record in human studies (7); however, several questions remain regarding its utility (8). These limitations are not solely based on the use of NTG and are relevant for all preclinical migraine models. For example, the selection of animal species, the method of induction/trigeminovascular activation, suitable control groups and the experimental readout are all critical factors.
As highlighted above, cilostazol acts via cAMP mechanisms whereas NTG is known to involve cGMP mechanisms (9). While the importance of this mechanistic discrepancy remains to be fully determined, there is on the surface one major differential effect that may ultimately enhance our understanding of migraine. To our knowledge, this is one of the first chemically induced studies in rodents to demonstrate a trigeminal-specific hyperalgesia in the orofacial dermatome with no parallel alteration in peripheral mechanosensitivity. A limitation of NTG induced “migraine” models is their induction of extracephalic hypersensitivity that can occur in conjunction with or independent of orofacial responses (10). As such, multiple studies have utilised hind-paw hyperalgesia as an experimental readout of migraine that must be treated with some caution, especially in the absence of combined trigeminal-related responses. It is clear that administration of cilostazol or NTG to humans does not induce extracephalic pain, and as such the ability of the current study to reproduce this important clinical outcome should not be underestimated.
What can we learn from this and similar induction models for future development and refinement of preclinical models?
As we enter an era of renewed pharmaceutical interest in primary headaches, we must consider carefully what preclinical models we utilise to inform our basic knowledge of and novel therapeutic targets for migraine. Our understanding has advanced significantly on the back of carefully conducted, well-characterised animal models (11). Many options exist, including the durovascular stimulation models (12), closed cranial window models (13), dural inflammatory soup models (14), cortical spreading depression models (15) and the ongoing development of chemically induced models discussed herein. The majority of the established models remain important for future preclinical research and available for further refinement, while the exact model chosen should depend on a number of factors, the most critical of which is the construct validity.
This is divided into two clear concepts: Face validity and predictive validity. The current study of Christensen et al. (1) is strengthened by its ability to induce cephalic specific hyperalgesia. On the other hand, cilostazol is reported to falter on its predictive validity. However, both these observations recapitulate what is observed in healthy controls where cilostazol induced headache was unresponsive to sumatriptan (5). As such, the cilostazol induction model may represent an important non-invasive model to induce headache-like behaviours and trigeminovascular activation in rodents that can be utilised to explore alternate triptan-resistant mechanisms and/or combined with suitable transgenic models to assess the impact of the genetic alteration on the headache phenotype.