Involvement of Spinal Angiotensin II System in Streptozotocin-Induced Diabetic Neuropathic Pain in Mice

Abstract

Renin-angiotensin system (RAS) activity increases under hyperglycemic states, and is thought to be involved in diabetic complications. We previously demonstrated that angiotensin (Ang) II, a main bioactive component of the RAS, might act as a neurotransmitter and/or neuromodulator in the transmission of nociceptive information in the spinal cord. Here, we examined whether the spinal Ang II system is responsible for diabetic neuropathic pain induced by streptozotocin (STZ). Tactile allodynia was observed concurrently with an increase in blood glucose levels the day after mice received STZ (200 mg/kg, i.v.) injections. Tactile allodynia on day 14 was dose-dependently inhibited by intrathecal administration of losartan, an Ang II type 1 (AT1) receptor antagonist, but not by PD123319, an AT2 receptor antagonist. In the lumbar dorsal spinal cord, the expression of Ang II, Ang converting enzyme (ACE), and phosphop38 mitogen-activated protein kinase (MAPK) were all significantly increased on day 14 after STZ injection compared with vehicletreated controls, whereas no differences were observed among AT1 receptors or angiotensinogen levels. Moreover, the increase in phospho-p38 MAPK was significantly inhibited by intrathecal administration of losartan. These results indicate that the expression of spinal ACE increased in STZ-induced diabetic mice, which in turn led to an increase in Ang II levels and tactile allodynia. This increase in spinal Ang II was accompanied by the phosphorylation of p38 MAPK, which was shown to be mediated by AT1 receptors.

Anti‐hypersensitive effect of angiotensin (1‐7) on streptozotocin‐induced diabetic neuropathic pain in mice

“…Recently, we have revealed that, in mice with STZ‐induced diabetes, the increase in spinal Ang II leads to an increase in phosphorylated p38 MAPK and neuropathic pain (Ogata et al, ). Moreover, the phosphorylation of other MAPKs such as ERK1/2 and JNK is also known to be involved in the STZ‐induced hyperalgesia (Middlemas et al, ; Tsuda et al, ).…”

“…We have recently reported that the expression of spinal ACE is increased in STZ mice, which in turn leads to an increase in Ang II levels. Through AT1 receptor signalling, the elevated spinal Ang II levels produced tactile hypersensitivity and were accompanied by the phosphorylation of p38 MAPK (Ogata et al, ). We have also reported that the nociceptive behaviour induced in mice by an i.t.…”

“…injection of a low dose of STZ (2 or 20 mg/kg) caused transient tactile hypersensitivity 1–3 days later without affecting blood glucose levels (Ogata et al, ). On the other hand, 200 mg/kg of STZ caused long‐lasting tactile hypersensitivity concurrent with an increase in blood glucose levels (Ogata et al, ). To exclude the possibility raised above that STZ is acting directly on neurons (Pabbidi et al, ), we studied mice on day 14 after the STZ (200 mg/kg) injection, a point in time that showed a marked decrease in pain threshold.…”

“…Tactile hypersensitivity was determined by assessing paw withdrawal in the von Frey filament test as previously described (Ogata et al, ). Mice were placed on a mesh floor inside a clear plastic cubicle for an acclimatization period of a least 30 min before the test.…”

“…administration of Ang II and p38 MAPK phosphorylation to be mediated by AT1 receptors (Nemoto et al, ). Also, we have revealed that the spinal ACE/Ang II/AT1 receptor pathway and subsequent p38 MAPK phosphorylation were involved in the streptozotocin (STZ)‐induced diabetic mouse model and led to tactile hypersensitivity (Ogata et al, ). These findings indicate that Ang II promotes spinal pain transmission via AT1 receptors.…”