AS1069562 [(R)-2-[(1H-inden-7-yloxy)methyl]morpholine monobenzenesulfonate] is the (1)-isomer of indeloxazine, which had been used clinically for the treatment of cerebrovascular diseases with multiple pharmacological actions, including serotonin (5-HT) and norepinephrine (NE) reuptake inhibition. Here we investigated the analgesic effects of AS1069562 in a rat model of chronic constriction injury (CCI)-induced neuropathic pain and the spinal monoamine turnover. These effects were compared with those of the antidepressants duloxetine and amitriptyline. AS1069562 significantly elevated extracellular 5-HT and NE levels in the rat spinal dorsal horn, although its 5-HT and NE reuptake inhibition was much weaker than that of duloxetine in vitro. In addition, AS1069562 increased the ratio of the contents of both 5-HT and NE to their metabolites in rat spinal cord, whereas duloxetine slightly increased only the ratio of the content of 5-HT to its metabolite. In CCI rats, AS1069562 and duloxetine significantly ameliorated mechanical allodynia, whereas amitriptyline did not. AS1069562 and amitriptyline significantly ameliorated thermal hyperalgesia, and duloxetine tended to ameliorate it. Furthermore, AS1069562, duloxetine, and amitriptyline significantly improved spontaneous pain-associated behavior. In a gastric emptying study, AS1069562 affected gastric emptying at the same dose that exerted analgesia in CCI rats. On the other hand, duloxetine and amitriptyline significantly reduced gastric emptying at lower doses than those that exerted analgesic effects. These results indicate that AS1069562 broadly improved various types of neuropathic pain-related behavior in CCI rats with unique characteristics in spinal monoamine turnover, suggesting that AS1069562 may have potential as a treatment option for patients with neuropathic pain, with a different profile from currently available antidepressants.
Abstract. This study was conducted to make a new mouse model of neuropathic pain due to injury to a branch of the sciatic nerve. One of three branches (sural, tibial, and common peroneal nerves) of the sciatic nerve was tightly ligated, and mechanical and cool stimuli were applied to the medial part (tibial and common peroneal nerve territories) of the plantar skin. The three types of nerve injuries produced behavioral mechanical hypersensitivities, and the extent of the hypersensitivities after sural and tibial nerve ligation was larger than that of common peroneal nerve ligation. Sural nerve ligation did not affect motor function of the affected hind paw, but tibial and common peroneal nerve ligation produced motor dysfunction. These results suggest that the ligation of the sural nerve is the most suitable for behavioral study. Sural nerve ligation induced behavioral hypersensitivities to mechanical and cool stimuli, which were almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation increased spontaneous activity and responses of the wide-dynamic range neurons in the lumbar dorsal horn, which were also almost completely inhibited by gabapentin (30 mg/kg). Sural nerve ligation provides a new mouse model of neuropathic pain, which is easy to prepare and sensitive to gabapentin.
Peripheral sensory neuropathy is a major complication of diabetes mellitus.1) Although the pathogenesis of this complication has not been fully elucidated, biochemical and pathological abnormalities have been observed in the early stages of experimental diabetic neuropathy. [2][3][4] One of the abnormalities is altered neurotropism, and a disturbance of neurotrophic support is reported in the peripheral nervous system of diabetic animals. [5][6][7][8][9] The axonal transport of nerve growth factor (NGF) and neurotrophin-3 (NT-3) produced in peripheral tissues was impaired in streptozotocin (STZ)-induced diabetic rats. 10,11) The exogenous supplementation of recombinant NGF showed efficacy in experimental and clinical diabetic neuropathy. 10,12) On the other hand, NT-3 treatment improved the nerve conduction velocity deficits, and mitochondrial and calcium homeostasis dysfunction of sensory neurons in the experimental diabetic rats. [13][14][15] Based on these findings, the dysfunction of neurotrophins is considered to be a cause of diabetic neuropathy pathogenesis.Axonal atrophy is a phenomenon in the peripheral nerves in the diabetic neuropathic state and is thought to be one cause of the slowing of peripheral nerve conduction velocity. [16][17][18] The axon-diameter depends on the integrity of neuronal cytoskeletal proteins, and there is a lot of evidence demonstrating a reduction in axonal transport and the aberrant phosphorylation of cytoskeletal protein in the peripheral nervous system in experimental diabetic animals. 17,[19][20][21][22][23][24][25] Therefore, the correction of these derangements leads to an improvement in diabetic neuropathy.Aldose reductase (AR) is a rate-limiting enzyme that converts glucose to sorbitol in the polyol pathway. As sorbitol accumulation in peripheral nerve tissue caused by hyperactivation of the polyol pathway is considered to be an etiological mechanism of diabetic neuropathy, 16,26) a number of AR inhibitors (ARIs) have been discovered. 27) ARI has been reported to improve the slowing of peripheral nerve conduction velocity and the axonal atrophy in experimental and clinical diabetic neuropathy. [28][29][30][31][32] The aim of this study was to explore whether the inhibition of the polyol pathway affects the deficits in neurotropism and neuronal cytoskeletal protein mRNA expression in the dorsal root ganglion (DRG) in STZinduced diabetic rats. MATERIALS AND METHODSAnimal Treatment Six-week-old male Sprague-Dawley rats were purchased from Charles River Japan Inc. (Yokohama, Japan). They were given water and a standard laboratory diet ad libitum, and housed in plastic cages with paper chips to avoid entrapment neuropathy.33) The temperature was maintained at 23Ϯ2°C with a humidity of 55Ϯ10%, with a 12-h light cycle. At seven weeks of age, the rats were rendered diabetic by intravenous injection of STZ (60 mg/kg) after overnight fasting. STZ (SIGMA, St. Louis, MO, U.S.A.) was dissolved in 10 mM citrate buffer (pH 4.5) containing 140 mM NaCl. Normal rats were given citrate b...
Voltage-dependent sodium channels (VDSCs) are crucial for pain generation. Here, to develop a new behavioral index of pain induced by spinal VDSC activation, we examined whether intrathecal veratridine injection produced nociceptive behavior. Intrathecal injection of the VDSC opener veratridine in mice dose-dependently induced nociceptive responses, with response times subsequently reduced by administration of morphine or pregabalin. Systemic administration of lidocaine and mexiletine, but not amitriptyline, also decreased this response time. Taken together, these results demonstrated that response time of nociceptive behavior induced by intrathecal veratridine injection is a quantitative index of pain triggered by spinal VDSC activation.
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