Background and Purpose
Iridoid glycosides containing the double bond scaffold of cyclopentapyran are reversible and orthosteric agonists of glucagon‐like peptide‐1 (GLP‐1) receptors and exert anti‐nociceptive and neuroprotective actions. Morroniside, derived from the medicinal herb Cornus officinalis, is an atypical secoiridoid containing a six‐membered cyclic inner ether fragment. Here we investigated whether morroniside was an orthosteric GLP‐1 receptor agonist and had anti‐hypersensitivity activities in a model of neuropathic pain.
Experimental Approach
We used a model of neuropathic pain, induced by tight ligation of L5/L6 spinal nerves in rats. Hydrogen peroxide‐induced oxidative damage was also assayed in N9 microglial cells and human HEK293 cells stably expressing GLP‐1 receptors.
Key Results
Morroniside protected against hydrogen peroxide‐induced oxidative damage in N9 microglial and HEK293 cells that expressed mouse or human GLP‐1 receptors, but not in HEK293T cells without GLP‐1 receptors. The GLP‐1 receptor orthosteric antagonist exendin(9‐39) also concentration‐dependently shifted the concentration‐protective response curves of morroniside and exenatide to the right without affecting maximal protection, with similar pA2 values. Furthermore, morroniside given by oral gavage or intrathecally in neuropathic rats dose‐dependently attenuated mechanical allodynia, with comparable Emax values and ED50s of 335 mg·kg−1 and 7.1 μg and completely blocked thermal hyperalgesia. Daily intrathecal injections of morroniside over 7 days did not induce anti‐allodynic tolerance. Pretreatment with intrathecal exendin(9‐39) completely blocked systemic and intrathecal morroniside‐induced mechanical anti‐allodynia.
Conclusion and Implications
Our data demonstrated that morroniside was an orthosteric agonist of GLP‐1 receptors and produced antihypersensitivity in a neuropathic pain model by activation of spinal GLP‐1 receptors.