Usefulness of antidepressants for improving the neuropathic pain-like state and pain-induced anxiety through actions at different brain sites.

Clinically, it is well known that chronic pain induces depression, anxiety, and a reduced quality of life. There have been many reports on the relationship between pain and emotion. We previously reported that chronic pain induced anxiety with changes in opioidergic function in the central nervous system. In this study, we evaluated the anxiolytic-like effects of several types of antidepressants under a chronic neuropathic pain-like state and searched for the brain site of action where antidepressants show anxiolytic or antinociceptive effects. Sciatic nerve-ligated mice exhibited thermal hyperalgesia and tactile allodynia from days 7 to 28 after nerve ligation. At 4 weeks after ligation, these mice showed a significant anxiety-related behavior in the light-dark test and the elevated plus-maze test. Under these conditions, repeated administration of antidepressants, including the tricyclic antidepressant (TCA) imipramine, the serotonin noradrenaline reuptake inhibitor (SNRI) milnacipran, and the selective serotonin reuptake inhibitor (SSRI) paroxetine, significantly prevented the anxiety-related behaviors induced by chronic neuropathic pain. These antidepressants also produced a significant reduction in thermal hyperalgesia and tactile allodynia. Moreover, the microinjection of paroxetine into the basolateral amygdala or cingulate cortex reduced anxiety-related behavior, and microinjection into the primary somatosensory cortex significantly attenuated thermal hyperalgesia. These findings suggest that serotonergic antidepressants are effective for treating anxiety associated with chronic neuropathic pain and may be useful for treating neuropathic pain with emotional dysfunction such as anxiety. Furthermore, SSRIs show anxiolytic and antinociceptive effects by acting on different brain regions.

Implication of Src family kinase-dependent phosphorylation of NR2B subunit-containing NMDA receptor in the rewarding effect of morphine.

The present study was undertaken to further clarify the role of tyrosine phosphorylation of NR2B subunit-containing N-methyl-D-aspartate (NMDA) receptor in the development of the morphine-induced rewarding effect in mice. The morphine (5 mg/kg, sc)-induced rewarding effect was completely inhibited by pretreatment with a selective NR2B subunit-containing NMDA receptor antagonist ifenprodil (20 mg/kg, i.p.). The protein level of phospho-Tyr-1472, but not phospho-Ser-1303, NR2B subunit was significantly increased in the mouse limbic forebrain containing the nucleus accumbens (N.Acc.) of mice that had shown the morphine-induced rewarding effect. In addition, the level of phospho-Tyr-416 Src family kinase was also increased in the limbic forebrain of mice that had shown the morphine-induced rewarding effect. These findings suggest that Tyr-1472 phosphorylation of NR2B subunit-containing NMDA receptor associated with activation of Src family kinase in the limbic forebrain may be involved in the morphine-induced rewarding effect.

Direct evidence for spinal cord microglia in the development of a neuropathic pain-like state in mice.

The present study was undertaken to further investigate the role of glial cells in the development of the neuropathic pain-like state induced by sciatic nerve ligation in mice. At 7 days after sciatic nerve ligation, the immunoreactivities (IRs) of the specific astrocyte marker glial fibrillary acidic protein (GFAP) and the specific microglial marker OX-42, but not the specific oligodendrocyte marker O4, were increased on the ipsilateral side of the spinal cord dorsal horn in nerve-ligated mice compared with that on the contralateral side. Furthermore, a single intrathecal injection of activated spinal cord microglia, but not astrocytes, caused thermal hyperalgesia in naive mice. Furthermore, 5-bromo-2'-deoxyuridine (BrdU)-positive cells on the ipsilateral dorsal horn of the spinal cord were significantly increased at 7 days after nerve ligation and were highly co-localized with another microglia marker, ionized calcium-binding adaptor molecule 1 (Iba1), but neither with GFAP nor a specific neural nuclei marker, NeuN, in the spinal dorsal horn of nerve-ligated mice. The present data strongly support the idea that spinal cord astrocytes and microglia are activated under the neuropathic pain-like state, and that the proliferated and activated microglia directly contribute to the development of a neuropathic pain-like state in mice.

Differences in tolerance to anti-hyperalgesic effects between chronic treatment with morphine and fentanyl under a state of pain.

The present study was undertaken to investigate the possible change in anti-hyperalgesic effect following repeated treatment with morphine or fentanyl using the dose to improve the thermal hyperalgesia under an inflammatory pain-like state. The anti-hyperalgesic effect induced by fentanyl in complete Freund's adjuvant (CFA)-pretreated mice rapidly disappeared during the consecutive administration of fentanyl, whereas morphine preserved its potency of anti-hyperalgesic effect. In addition, repeated treatment with fentanyl, but not morphine, resulted in the increase in levels of phosphorylated-mciro-opioid receptor (MOR) associated with the enhanced inactivation of protein phosphatase 2A and the reduction in Rab4-dependent MOR resensitization. Next, we investigated the specific involvement of the opioid receptor types and MOR subtypes in analgesic properties of morphine and fentanyl in the mouse spinal cord. In the competitive displacement binding assay with [1H]DAMGO, no significant difference in the binding affinity to MOR between morphine and fentanyl was noted in membranes obtained from the mouse spinal cord. Furthermore, there was no significant difference between morphine and fentanyl in either antinociceptive effect or G-protein activation in mice partially lacking MOR-1B, which shows a greater resistance to agonist-induced desensitization than for other MOR subtypes. These findings point out the possibility that the chronic treatment with fentanyl may cause the different modulation from chronic treatment with morphine on either the internalization or resensitization of MORs in the spinal cord under a pain-like state. The present data provide the first evidence for the mechanism underlying the development of tolerance to fentanyl-induced anti-hyperalgesic effect under chronic pain.