Mechanisms of neuropathic pain associated with metabotropic glutamate receptor 5 in the brain

Abstract

Neuropathic pain is a pathological pain caused by damage to the peripheral or central nervous system. As symptoms of neuropathic pain are often intractable, patients suffer from long-lasting severe pain and easily develop abnormal mental problems such as depression and anxiety. However, underlying mechanisms are not fully understood. I investigated the brain-level mechanisms of neuropathic pain in an animal model of spinal nerve ligation, using brain imaging techniques of positron emission tomography (PET), electrophysiological recording, pharmacological and genetic manipulation and animal behavior analysis. Metabotropic glutamate receptor 5 (mGluR5) was a particular target, as this molecule plays a pivotal role in the plastic change of the neurons. This thesis consists of three research parts and a review part. In chapter 1, it is shown that the mGluR5 level in the medial prefrontal cortex (mPFC) is increased in neuropathic pain state, and this upregulation is responsible for the amplified aversive perception and negative moods. Chapter 2 deals with brain patterns of the mGluR5 levels which encode the degree of neuropathic pain behavior. A method I developed for the objective evaluation of neuropathic pain using the patterns in the PET image is introduced. In chapter 3, mGluR5 activity in the periaqueductal gray (PAG) region is focused. I found that the mGluR5 within the PAG is persistently active in normal state, and a conditional inactivation of it drives chronic pain. Chapter 4 discusses molecular mechanisms underlying the sustained activation of mGluR5. As a whole, this thesis illustrates how the pain becomes chronic and why it is not treated well. The alteration of the brain in neuropathic pain state and underlying mechanisms are revealed, focusing on the mGluR5. Based on the mechanisms, this thesis identifies mGluR5 in the brain regions as therapeutic targets for the treatment of chronic neuropathic pain. In addition, a method for decoding the status of the individual neuropathic pain subject is demonstrated. This method evaluates the pain status objectively using the information of mGluR5 patterns in the brain, and thus is applicable for a diagnostic purpose in the clinic. This thesis provides new insight into the brain signature of neuropathic pain, and offers a novel perspective on the status of mGluR5 in physiological and pathological conditions.