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Selective blockade of metabotropic glutamate receptor 5 alleviates post-surgical pain in rats Metabotropic glutamate (mGlu) receptor-mediated activity contributes to modulation of nociceptive processing, inflammatory pain and hyperalgesia (Neugebauer et al., 1999). Recently, a novel mGlu5 receptor subtype-selective antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) has been described, which has anti-nociceptive and analgesic properties in models of acute pain (Bordi & Ugolini, 2000; Walker et al., 2001; Hama, 2003). This study used MPEP to characterise the contribution of mGlu5 receptors to post-operative pain and hypersensitivity in an animal model of surgical pain . Adult female Sprague-Dawley rats (200-250 g) were anaesthetised with isoflurane (2%) and underwent a midline laparotomy with gentle manipulation of the viscera. Control animals were submitted to anaesthesia only. Hindpaw withdrawal latency (in secs) to thermal stimulation (measure of thermal hyperalgesia) and response threshold (in grams) to mechanical stimulation (measure of mechanical allodynia) were measured before surgery and at 2, 4, 6 h, and 1, 2, 3 and 7 days after surgery. The effects of pre- (30 min) or post- (5 h) surgical treatment with MPEP (1, 10 or 100 mgkg-1; i.p.) or drug-vehicle on response thresholds were assessed following surgery (n = 6-9 rats/group). Data (mean ± SEM) were analysed with a two-way mixed factorial ANOVA. The maximum effect (Emax) was also calculated as the maximum change in withdrawal threshold after treatment from baseline responses. These data were analysed using one-way ANOVA with post-hoc Tukey’s test. Animals that underwent surgery displayed significant hypersensitivity to hindpaw stimulation. Maximum allodynia was observed 6 h post-surgery (Emax: 44.5 ± 2.4%; p < 0.01 vs. anaesthesia only control animals) and persisted until day 3. Surgery had no effect on thermal withdrawal latency. Post-operative administration of MPEP significantly attenuated mechanical allodynia induced by surgery compared to vehicle (F(3,26) = 9.6; p < 0.001). Similar levels of analgesia were achieved at 6 h by 10 mgkg-1 (Emax: 1.0 ± 7.9%; p < 0.01 vs. vehicle) and 100 mgkg-1 MPEP (Emax: 6.2 ± 10.4%; p < 0.01 vs. vehicle). In contrast, pre-administration of MPEP had no effect on mechanical allodynia induced by surgery. Treatment with MPEP had no effect on mechanical or thermal responses in animals subjected to anaesthesia only. In this study, systemic MPEP reversed mechanical allodynia induced by surgery when administered post-operatively. These data suggest that activity at mGlu5 receptors may contribute to persistence of pain and hypersensitivity observed following surgery, suggesting that mGlu5 receptors may be effective therapeutic targets for relief from post-surgical pain.
Bordi, F., Ugolini, A. (2000) Brain Research 871, 223-233. |
