Palazzo E, Marabese I, de Novellis V, Oliva P, Rossi F, Berrino L, Rossi F, Maione S
Institute of Pharmacology and Toxicology, Faculty of Medicine and Surgery, Second University of Naples, Via Costantinopoli 16, I-80138, Naples, Italy.
Neuropharmacology. 2001 Mar;40(3):319-26. doi: 10.1016/s0028-3908(00)00160-x.
The purpose of this study was to evaluate the possible contribution of metabotropic glutamate receptors (mGluRs) to cannabinoid-induced antinociception in the periaqueductal grey (PAG) matter of rats. Intra-PAG microinjection of WIN 55,212-2, a cannabinoid receptor agonist, increased the latency of the nociceptive reaction (NR) in a dose-dependent fashion in the plantar test. This effect was prevented by pretreatment with SR141716A, a selective antagonist of CB1 receptors. When injected alone, SR141716A produced, with the highest dosage used, a significant reduction in the latency of the NR. CPCCOEt, a selective mGlu1 receptor antagonist, was unable to prevent the analgesia produced by WIN 55,212-2. On the contrary, MPEP, a selective mGlu5 receptor antagonist, completely antagonized the effect of WIN 55,212-2. However, the analgesia induced by CHPG, a selective mGlu5 receptor agonist, was blocked by MPEP but not by SR141716A. When injected alone, CPCOOEt produced no effect, whereas MPEP produced, with the highest dosage used, a significant reduction in the latency of the NR. These data emphasize that mGlu5 receptors, but not mGluR1, may modulate nociception in the PAG. Similarly, a pretreatment with either 2-(S)-alpha-EGlu or (RS)-alpha-MSOP, selective antagonists for group II and III mGluRs, respectively, prevented the WIN 55,212-2-induced analgesia. When the higher dosage of (RS)-alpha-MSOP was used a decrease in the latency of the NR was observed. This was not the case for 2-(S)-alpha-EGlu. Pretreatment with DL-AP5, a selective antagonist of N-methyl-D-aspartate (NMDA) receptors, blocked the effect of WIN 55,212-2, and by increasing the dosage strongly reduced per se the latency of the NR. This study suggests that endogenous glutamate could tonically modulate nociception through mGlu and NMDA receptors in the PAG matter. In particular, the physiological stimulation of these receptors seems to be required for the cannabinoid-induced analgesia in this midbrain area.
本研究的目的是评估代谢型谷氨酸受体（mGluRs）对大鼠中脑导水管周围灰质（PAG）中大麻素诱导的镇痛作用可能产生的影响。在足底试验中，向PAG内微量注射大麻素受体激动剂WIN 55,212-2，可使伤害性反应（NR）的潜伏期以剂量依赖性方式延长。CB1受体的选择性拮抗剂SR141716A预处理可阻止这种作用。单独注射时，使用最高剂量的SR141716A可使NR潜伏期显著缩短。选择性mGlu1受体拮抗剂CPCCOEt无法阻止WIN 55,212-2产生的镇痛作用。相反，选择性mGlu5受体拮抗剂MPEP可完全拮抗WIN 55,212-2的作用。然而，选择性mGlu5受体激动剂CHPG诱导的镇痛作用被MPEP阻断，但未被SR141716A阻断。单独注射时，CPCCOEt无作用，而使用最高剂量的MPEP可使NR潜伏期显著缩短。这些数据表明，mGlu5受体而非mGluR1可能调节PAG中的伤害感受。同样，分别用II组和III组mGluRs的选择性拮抗剂2-(S)-α-EGlu或(RS)-α-MSOP预处理，可阻止WIN 55,212-2诱导的镇痛作用。使用较高剂量的(RS)-α-MSOP时，观察到NR潜伏期缩短。2-(S)-α-EGlu则不然。N-甲基-D-天冬氨酸（NMDA）受体的选择性拮抗剂DL-AP5预处理可阻断WIN 55,212-2的作用，且通过增加剂量本身可强烈缩短NR潜伏期。本研究表明，内源性谷氨酸可能通过PAG中的mGlu和NMDA受体对伤害感受进行紧张性调节。特别是，这些受体的生理刺激似乎是该中脑区域大麻素诱导镇痛所必需的。
