Neuropharmacology
-
Chemokines are associated with both inflammatory and immune responses and play an important role in the pathophysiological process associated with neuropathic pain following peripheral nerve injury. Here, we investigated the involvement of peripheral keratinocyte-derived chemokine (KC) in the pathogenesis of neuropathic pain induced by the partial ligation of the sciatic nerve (PLSN) in mice. PLSN increased KC levels and its mRNA in both the sciatic nerve and spinal cord when compared with sham-operated mice. ⋯ We also demonstrated an increased level of cytokines (IL-1β, IL-6, and MCP-1, but not TNF-α) after i.n. injection of KC in the mouse sciatic nerve. Together, these findings suggest a role for KC in the development of neuropathic pain in mice by attracting neutrophils to the injured site and increasing the production of proinflammatory mediators. Therefore, strategies to inhibit the action or the release of this chemokine could constitute a therapeutic tool for the management of neuropathic pain in humans.
-
Oxaliplatin, unlike other platinum anticancer agents, has only mild toxic effects on the hematopoietic, urinary and gastrointestinal systems. Its dose-limiting side effect is neurotoxicity that may evolve to a neuropathic syndrome which is difficult to treat. In this study we treated rats with oxaliplatin (2.4 mg/kg/day intraperitoneally, for 3 weeks), and observed that expression levels of the α7 nicotinic acetylcholine receptor (nAChR) subunit were dramatically decreased both in the peripheral and central nervous system. ⋯ Astrocyte density was enhanced by the agonist treatment in the spinal cord, thalamus and somatosensory area 1 as opposed to the effects of oxaliplatin treatment. (R)-ICH3 and PNU-282987 per se increased glial cell number in a region-specific manner. In summary, α7 nAChR is involved in oxaliplatin-dependent neuropathology and the agonists (R)-ICH3 and PNU-282987 reduce pain and protect nervous tissue with concomitant glial activation. Since glial cells play a role both in pain and in neuroprotection, an α7 AChR-dependent modulation of glial functions is suggested to distinguish rescue signals from the pathological pain-mediating pathway.
-
Facilitation of serotonin 2C- and 1A-receptor (5-HT2C-R and 5-HT1A-R) mediated neurotransmission in the basolateral nucleus of the amygdala (BLA) has been associated with anxiogenic and anxiolytic effects, respectively. It has been also shown that stimulation of BLA 5-HT2C-Rs underlies the anxiogenic effect caused by acute systemic administration of the antidepressants imipramine or fluoxetine. Here we investigated whether chronic treatment with these two antidepressants, which causes anxiolytic effects, decreases the responsiveness of these receptors in the BLA. ⋯ Acute administration of imipramine (5 mg/kg) failed to interfere with MK-212 effects in both tests. Intra-BLA injection of the 5-HT1A antagonist WAY-100635 blocked the anxiolytic, but not the panicolytic, effect of imipramine in the tests used. Our findings indicate that both a reduction in 5-HT2C-R- and a facilitation of 5-HT1A-R-mediated neurotransmission in the BLA are involved in the anxiolytic effect of antidepressant drugs.
-
The 5-HT(4) receptor agonist tegaserod (TEG) has been reported to modulate visceral pain. However, the underlying mechanism remains unknown. The objective of the present study was to examine the analgesic mechanism and site of action of TEG. ⋯ While TEG had no effect on the responses of CRD-sensitive PNA, it inhibited the responses of CRD-sensitive LS neurons in spinal intact condition. This inhibition was blocked by GR113808, NLX and β-funaltrexamine (β-FNA) when injected into the RVM. Results indicate that TEG produces analgesia via activation of supraspinal 5-HT(4) receptors which triggers the release of opioids at supraspinal site, which activates descending noradrenergic pathways to the spinal cord to produce analgesia.
-
Comparative Study
AS1069562, the (+)-isomer of indeloxazine, but not duloxetine has a curative-like analgesic effect in a rat model of streptozotocin-induced diabetic neuropathy.
AS1069562 is the (+)-isomer of indeloxazine, which had been clinically used as a cerebral activator for the treatment of cerebrovascular diseases with serotonin and norepinephrine reuptake inhibition (SNRI) and neuroprotection. Here, we compared the analgesic effects of repeated treatment with AS1069562 and duloxetine, a selective SNRI, on pain-related behavior in a rat model of streptozotocin (STZ)-induced diabetic neuropathy. Further, we also evaluated the effects on the expression of neurotrophic factors and nerve conduction velocity. ⋯ The results of this study indicate that the analgesic effect of repeated dosing of AS1069562 but not duloxetine is persistent even after a 1-week drug discontinuation in STZ-induced diabetic rats. Restoration of neurotrophic factors may be involved in the curative-like pharmacological effect of this agent. Thus, AS1069562 may potentially offer a better treatment option for patients with painful diabetic neuropathy than duloxetine via different mechanisms.