척수 통증과민화에서 중추 transient receptor potential vanilloid-1 수용체의 역할

Abstract

Transient receptor potential vanilloid subtype 1 (TRPV1) is predominantly expressed in central terminals of C-fiber primary sensory neuron and their antagonists have shown efficacy in inflammatory and neuropathic pain. TRPV1 and metabotropic glutamate receptor 5 (mGluR5) located on peripheral sensory terminals have been shown to play critical roles in the transduction and modulation of pain sensation. However, very little is known regarding the significance of functional expression of mGluR5 and TRPV1 on the central terminals of sensory neurons in the dorsal horn of the spinal cord. In the first chapter, I show that functional coupling of mGluR5-TRPV1 via diacylglycerol (DAG) generated by mGluR5 activation on the central presynaptic terminals of nociceptive neurons may be an important mechanism underlying central sensitization under pathological pain conditions. A number of recent studies revealed that TRPV1 antagonist attenuated not only thermal hyperalgesia but also mechanical allodynia, which is thought to be independent of peripheral-TRPV1, suggesting that central postsynaptic TRPV1 may be involved in pathological mechanical pain. However, the underlying mechanisms for the activation of central TRPV1 and role of central postsynaptic TRPV1 under pathophysiological conditions remain unknown. In the second chapter, I present that activation of spinal TRPV1 induces long-term depression (LTD) in GABAergic substantia gelatinosa (SG) neurons and produces mechanical allodynia by reducing inhibitory inputs to projection neurons. Chronic mechanical pain following nerve injury was reversed by a spinally applied TRPV1 antagonist. Taken together, spinal TRPV1 plays a critical role as a synaptic regulator and suggest the utility of CNS-specific TRPV1 antagonists for treating neuropathic pain.