AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in a rat model of neuropathic pain with unique characteristics in spinal monoamine turnover.

AS1069562 [(R)-2-[(1H-inden-7-yloxy)methyl]morpholine monobenzenesulfonate] is the (+)-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.

New index of pain triggered by spinal activation of voltage-dependent sodium channels.

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.

The involvement of aldose reductase in alterations to neurotrophin receptors and neuronal cytoskeletal protein mRNA levels in the dorsal root ganglion of streptozotocin-induced diabetic rats.

Dorsal root ganglia (DRG) are recognized as one of the organs which are damaged in peripheral sensory diabetic neuropathy. In an experimental animal model, the alteration of the mRNA expression level of neurotrophins, their receptors and neuronal cytoskeletal protein have been reported. In this study, we examined whether these changes are improved by treatment with the aldose reductase inhibitor, zenarestat, in early-stage diabetic neuropathy of streptozotocin (STZ)-induced diabetic rats. Two weeks after the induction of diabetes mellitus by STZ treatment, zenarestat or a vehicle were given orally for two weeks. After the zenarestat treatment, the mRNA expression levels of neurotrophin receptors and neuronal cytoskeletal proteins in dorsal root ganglia were determined with a real-time polymerase chain reaction (PCR) method. Compared with the expression level of normal rats, a significant increase in Trk-C and Talpha1 alpha-tubulin and a decrease in neurofilament H mRNA expression level were observed in the DRG of STZ rats, while there were no significant changes in Trk-A, Trk-B, p75, neurofilament L, neurofilament M and betaIII tubulin mRNA expression. Zenarestat treatment significantly ameliorated the abnormal increase in Trk-C mRNA expression level. These data suggest that hyperactivation of the polyol pathway induces a deficit in neurotropism on peripheral sensory diabetic neuropathy.

A mouse model of sural nerve injury-induced neuropathy: gabapentin inhibits pain-related behaviors and the hyperactivity of wide-dynamic range neurons in the dorsal horn.

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.