Inhibition of diacylglycerol lipase alpha (DAGLα) as a model for episodic headache in rats: Features and applications

It is well known that the endocannabinoid system (ECBS) plays a role centrally and peripherally in the processing of pain signaling. Recent findings support the hypothesis of Clinical Endocannabinoid Deficiency (CED) underlying the pathophysiology of certain pain disorders, including migraine and headache. Experimental data suggest the active contribution of the endocannabinoid system in migraine pain, but to date, the exact eCB-dependent mechanisms underlying migraine are not fully understood. Several well-validated animal models of headache-like pain have been developed, each of them has its own advantage and limitation, but none can cover all migraine-associated symptomology, due to heterogeneity of migraine phenotypes. The new, translationally relevant animal model described in this chapter utilizes pharmacological manipulation of the endocannabinoid system by blocking diacylglycerol lipase (DAGL), the enzyme responsible for the synthesis of 2-arachidonoylglycerol (2-AG) in female and male Sprague Dawley rats. Selective inhibition of DAGLα induced the main features of episodic headache, including cutaneous allodynia at the cephalic site and spontaneous pain behaviors, such as head-pressing and photophobia. However, non-sensory features of migraine such as anxiety and depression were not observed after acute DAGLα inhibition. Headache-like behavior was associated with reduced 2-AG signaling in the cortex and periaqueductal gray (PAG), but not the trigeminal nucleus caudalis or trigeminal ganglia, and it was mitigated by administration of the clinically relevant abortive anti-migraine agents, sumatriptan, and olcegepant. This model provides evidence for a role of DAGL-2-AG signaling in the induction of headache-like pain with reduced time, cost, and invasiveness of currently accepted models of headache.