Laboratory of Pharmacology
Laboratory of Pharmacology
Japanese
Using behavioral, electrophysiological and biochemical approaches, we elucidate the pathophysiology of central nervous system diseases such as chronic pain, pruritus, depression and stress, to find crucial factors leading to the development of novel therapeutic agents.
Research Content
１．Pain and itch research
Acute pain is one of the symptoms associated with trauma and illness, and plays an important role as a warning signal. However, chronic pain such as neuropathic pain which persists after healing of the disease or tissue damage, or independently of them, no longer has physiological significance, and the pain itself is a detrimental disease to be treated.
In chronic pain conditions, enhanced efficacy of synaptic transmission in the dorsal horn of the spinal cord underlies central major aspects of hyperalgesia and tactile allodynia. Such increases in synaptic efficacy are ascribed to short- and long-term changes in the excitability of primary sensory afferent terminals and spinal dorsal horn neurons, including alterations in the function and/or expression of various receptors and ion channels which play a crucial role in the determination of membrane potential.
Furthermore, itch research focusing on the neural circuit of the dorsal horn of the spinal cord started worldwide in the 2010s, and we are also studying spinal itch mechanisms based on the knowledge gained from pain research.
Brain and spinal cord slices
Slice preparations of the spinal cord and brain maintaining neuronal networks are suitable for physiological and pharmacological studies of excitatory and inhibitory synaptic transmission.
Patch-clamp electrophysiology using spinal slices with attached dorsal roots
We employ whole-cell patch-clamp recordings of excitatory synaptic currents mediated by Aδ-fibers and C-fibers from substantia gelatinosa neurons of spinal dorsal horn in slices prepared from adult mice. Patch-clamp is a powerful technique which allows us to study the pathophysiology of pain and itch and the mechanism of action of drugs at the functional level of synaptic transmission.
＃２gangliosides
Lipids are the basic substances for living organisms by forming cell membranes. In addition, accumulating evidence indicates that some lipids have new functions as extracellular mediators. However, there are still many other lipid molecules, and the function of most lipids in pain and itch is unknown. Therefore, we would like to clarify the relationship between lipids and pain and itch, and apply the acquired knowledge to drug discovery for the purpose of analgesia and pruritus.
The main lipids that form biological membranes are divided into phospholipids, cholesterol, and sphingolipids. In particular, the glycolipid (a type of sphingolipid) that we are paying attention to is characterized by the large variety of hydrophilic sugar chains. Glycolipids have various monosaccharides such as glucose and galactose bound to ceramide, and have numerous structures depending on the type of sugar and the way the bonds are branched.
Among them, glycolipids with sialic acid are called gangliosides, and GM1, GD1a, GD1b, GT1b, etc., which have long sugar chains, are abundantly contained in the nervous system. It has been clarified that administration of ganglioside GT1b to the plantar surface of a mouse causes pain, and the mechanism is being elucidated.
２．Elucidation of the pathophysiology of central dysfunction in depression and anxiety disorders and development of new therapeutic agents
The spinal cord is an important site of action of gabapentinoids such the α2δ ligand pregabalin and mirogabalin to relive pain. We have recently clarified that they also act on the upper brain regions to activate the descending noradrenaline pathway, which is an intrinsic pain-inhibitory system, and exert analgesic effects on neuropathic pain.
Evaluation of working memory by behavior analysis in the maze
The Y- maze test is an experimental system that evaluates how much a mouse remembers the most recently searched passage when exploring the maze.
In collaboration with the Laboratory of Medicinal Chemistry, we are conducting research and development of effective compounds for the stress-induced impairment of working memory.
Evaluation of memory-improving drugs by analyzing synaptic transmission in slices
The Y- maze test is an experimental system that evaluates how much a mouse remembers the most recently searched passage when exploring the maze.In collaboration with the Laboratory of Medicinal Chemistry, we are conducting research and development of effective compounds for the stress-induced impairment of working memory.
We have shown that drugs previously reported to have antidepressant effects improve synaptic plasticity (red) impaired by intracerebral inflammation (green).