Division of Molecular Pharmacology and Neuroscience
Nagasaki University Graduate School of Biomedical Sciences
Nagasaki University Center for Pain Research
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Theme 3
Molecular and Behavioral Sciences of Pain
1. Topics
Study of pain is now one of most actively investigated science. Amongst molecular basis of mechanisms of intractable chronic pain are very competitive topics in the world. Our goal of this topic is to identify molecular targets underlying intractable chronic pain and to discover analgesics to inhibit it by use of molecular biology, behavioral pharmacology and biochemical analysis. Another important goal is to visualize the plasticity of nociceptive inputs and neuronal networks throughout central nervous system.

2. Recent Discoveries
We have firstly identified and characterized type III nociceptive fibers which are related to neuropathic pain. We found various kinds of genes or molecules such as ERK1/2, bradykinin receptor 1 and TRPV1 (capsaicin receptor) related to neuropathic pain in such neurons (Rashid et al., (2003) J Pharmacol Exp Ther.; 304(3);940-948; Rashid et al., (2003) J Pharmacol Exp Ther.; in press). We also found various kinds of analgesics to inhibit the neuropathic pain, such as botulinum toxin C3, capsaicin cream, nicotinic agonists and some kinds of opioids.
Most recently, we firstly demonstrated the critical role for lysophosphatidic acid (LPA) signaling in the initiation of neuropathic pain (Inoue et al., Nature Medicine, 10, 712-718, 2004). In this study, the role of LPA signaling in the development of neuropathic pain was examined by pharmacological and genetic approaches, including the use of LPA receptor-null mice. The mice lacking a single LPA1 receptor that activates the Rho/Rho-kinase pathway, do not develop signs of neuropathic pain, such as behavioral allodynia and hyperalgesia, dorsal root demyelination, and increased expression of both the protein kinase Cg-isoform within the spinal cord dorsal horn and a2d-1 calcium channel subunit in dorsal root ganglia following peripheral nerve injury. We also found that intrathecal injection of LPA mimics behavioral, morphological and biochemical changes following nerve ligation.

3. Methodologies/Technologies
Main methodology is of course pain behavioral strategy. But we developed a very sensitive, more analytical and ethically preferable nociception test (algogenic-induced nociceptive flexion/ANF test) in mice (Inoue et al., (1998) Proc. Natl. Acad. Sci. USA, 95(18), 10949-10953). We also use all kinds of conventional nociception tests including Hargreaves thermal and paw pressure (automatic von Frey) tests. We are always trying to correlate the functional (behavioral) changes to histochemical ones. Furthermore to make sure of the proposed mechanisms, we are studying the functional and histochemical or morphological changes following genetic or toxin-induced disruption of target molecules. In order to see plastic changes in neuronal networking, we are attempting various new technologies.