2009 Fiscal Year Final Research Report
The development of mechanical hyperalgesia under cerebral ischemic stress and its alleviation
| Project/Area Number |
20790213
|
|---|
| Research Category |
Grant-in-Aid for Young Scientists (B)
|
| Allocation Type | Single-year Grants |
|---|
| Research Field |
General pharmacology
|
|---|
| Research Institution | Kobe Gakuin University |
|---|
Principal Investigator |
HAMABE Wakako Kobe Gakuin University, 薬学部, 助教 (30382328)
|
|---|
| Project Period (FY) |
2008 – 2009
|
| Keywords | 疼痛 / 脳卒中 / 糖尿病 |
|---|
| Research Abstract |
Cerebral ischemia is a leading cause of death and disability in the world. Furthermore, it is associated with severe complications such as memory disturbance, palsy and spasticity. Central post-stroke pain (CPSP) is also known as one of the ischemic complications and is clinically characterized by spontaneous pain, attacks of allodynia and dysesthesia, while the detailed mechanism has not been understood yet. Furthermore, there are few repots about CPSP in animal model. Hitherto, we have demonstrated that the glucose intolerance could be induced by ischemic stress per se, and normalization of blood glucose during the early phase of cerebral stroke decreased the neuronal dysfunction. Since hyperglycemia is known as one of the triggers of hyperalgesia or pain, we focused on the mechanism of development of post-ischemic glucose intolerance and its relationship with the development of CPSP using cerebral ischemic model mice.
Male ddY mice were subjected to 2 hr of left middle cerebral arter
… More
y occlusion (MCAO). The development of neuronal damage was estimated by histological^-and behavioral-analysis. The development of glucose intolerance was analyzed by measurement of blood glucose levels and serum insulin/adiponectin levels, and by insulin tolerance test and oral glucose tolerance test. On the other hand, the activities of 5'-AMP-activated protein kinase (AMPK), a known serine/threonine kinase that plays a key role in energy homeostasis, were analyzed by western blot. Furthermore, alterations of sensitivity of primary afferent neurons were measured by neurometer. Paw withdrawal threshold (PWT) of hind paw was measured by von Frey filament test.
The development of infarction and behavioral abnormality was clearly observed on day 1 and 3 after MCAO that was preceded by the significant elevation of fasting blood glucose levels. In the liver tissue, the activities of AMPK did not show any alterations. On the other hand, AMPK activating agents completely suppressed the development of glucose intolerance and of neuronal damage after MCAO. In the estimation of peripheral neuronal activity, sensitivity of Aδ and Aβ fibers was significantly increased on day 3 after MCAO, while sensitivity of C fiber did not altered at all. In addition, the PWT in left hind paw was significantly decreased on day 3 after MCAO when compared with day 0, while that in right hind paw showed no significant difference. Subcutaneous administered morphine blocked the decrease of PWT in left hind paw.
In this study, we found that the development of post-ischemic glucose intolerance was not mediated by such alterations as down-regulation of hepatic AMPK. On the other hand, over activation of hepatic AMPK may accelerate the glucose metabolism after ischemic stress and ameliorate the neuronal damage. At the same time, we detected the development of hyperalgesia, one of the known symptoms of CPSP, in our cerebral ischemic model mice. This may be due to myelinated A fiber specific hypersensitivity under ischemic stress. Furthermore, the responsiveness to opioidergic system might be conserved in this ischemic stress-induced pain model. Less
|
