Analgesic activity of a non-peptide imidazolidinedione somatostatin agonist: in vitro and in vivo studies in rat.

Several lines of evidence support an important role for somatostatin receptors (SSTRs) in pain modulation. The therapeutic use of established SSTR peptide agonists for this indication is limited by their broad range of effects, need for intrathecal delivery, and short half-life. Therefore, the goal of the present study was to investigate the analgesic effect of SCR007, a new, highly selective SSTR2 non-peptide agonist. Behavioral studies demonstrated that paw withdrawal latencies to heat were significantly increased following intraplantar SCR007. Furthermore, both intraperitoneal and intraplantar injection of SCR007 significantly reduced formalin- and capsaicin-induced flinching and lifting/licking nociceptive behaviors. Recordings from nociceptors using an in vitro glabrous skin-nerve preparation showed that SCR007 reduced heat responses in a dose-dependent fashion, bradykinin-induced excitation, heat sensitization and capsaicin-induced excitation. In both the behavioral and single fiber studies, the SCR007 effects were reversed by the SSTR antagonist cyclo-somatostatin, demonstrating receptor specificity. In the single fiber studies, the opioid antagonist naloxone did not reverse SCR007-induced anti-nociception suggesting that SCR007 did not exert its effects through activation of opioid receptors. Analysis of cAMP/protein kinase A (PKA) involvement demonstrated that SCR007 prevented forskolin- and Sp-8-Br-cAMPS (a PKA activator)-induced heat sensitization, supporting the hypothesis that SCR007-induced inhibition could involve a down-regulation of the cAMP/PKA pathway. These data provide several lines of evidence that the non-peptide imidazolidinedione SSTR2 agonist SCR007 is a promising anti-nociceptive and analgesic agent for the treatment of pain of peripheral and/or central origin.

Expression of 5-HT2A receptor mRNA in rat nucleus raphe magnus neurons after peripheral inflammation.

AIM: Examine the expression of 5-HT2A receptor mRNA and co-localization of 5-HT2A receptor mRNA with 5-HT immunoreactivity in nucleus raphe magnus (NRM) neurons following carrageenan inflammation. METHODS: In situ hybridization (ISH) and combining fluorescent ISH with immunofluorescent histochemical double staining technique were used in the present study. RESULTS: 5-HT2A receptor mRNA was expressed in moderate level in NRM neurons. Following carrageenan inflammation, the expression of 5-HT2A receptor mRNA in NRM was greatly increased. The peak occurred at 3 - 8 h and then there was a clear decrease at 24 h after injection of carrageenan. Only a few 5-HT2A receptor mRNA and 5-HT immunoreactive double labeled cells were observed in NRM, and the number of the double labeled cells had no obvious change following carrageenan inflammation. CONCLUSION: The synthesis of 5-HT2A receptor was increased in non-serotonin rather than serotonin neurons of NRM during peripheral inflammation.

Expression of 5-HT2A receptor mRNA in rat spinal dorsal horn and some nuclei of brainstem after peripheral inflammation.

The expression of 5-hydroxytryptamine 5-HT2A receptor mRNA was studied in the lumbar spinal dorsal horn, nucleus of raphe magnus (NRM), ventrolateral periaqueductal gray (vlPAG) and dorsal raphe nucleus (DRN) following carrageenan inflammation using in situ hybridization technique. The findings of this study demonstrated that 5-HT2A receptor mRNA was expressed with low to moderate levels in lumbar spinal dorsal horn, NRM, vlPAG and DRN. Following carrageenan inflammation, the expression of 5-HT2A receptor mRNA in ipsilateral dorsal horn, bilateral NRM, vlPAG and DRN was significantly increased. The peak occurred at 3 h and then there was a clear decrease but still a substantial number of labeled cells at 24 h after injection of carrageenan. This result suggested that the synthesis of 5-HT2A receptor is enhanced in spinal dorsal horn, NRM, vlPAG and DRN during inflammatory pain.

[The phase-dependent response of the heart to vagal stimulation in soft-shelled turtles].

Using cardiac cycle length (A-A interval) as an index, the effect of phase-coupled burst of vagal stimulation on the heart rate were investigated in 27 turtles. The negative chronotropic response depended on timing of the stimulus burst within the cardiac cycle. At first, the A-A interval was lengthened progressively and then showed a rapid decrease. The amplitude (AT) of the mean phase-response curve to right vagal stimulus in turtles treated by propranolol at normal temperature was 1484.10 +/- 213.10 ms. The minimum-to-maximum phase difference of the response curves was 804.00 +/- 210.90 ms. Both the AT and (St-A)max of the response curve varied directly with AA. In contrast, (St-A)min was not influenced by AA. Moreover, it was also found that the tau FR, AT, AA and (St-A)min in hibernant animals were all higher than those in normal ones. However, in three of the six hibernant turtles maximum positive chronotropic response could be elicited at the time when (A-A)min was elicited by vagal stimulation. The results indicated that the phase-dependent response to right vagus in turtles was similar to that in homothermal animals, but significantly different both in the amplitude of the phase-response and the latency of negative chronotropic response. Since the phase-response was abolished by atropine, not by propranolol, it was suggested that the occurrence of phase-response was due to changes of responsiveness of automatic cells to ACh released from the vagus nerve.