Dopamine receptors in the anterior cingulate cortex implicate in nicotine enhanced morphine analgesia.

RATIONALE: It is well known that the anterior cingulate cortex (ACC) plays an important role in acute pain perception. OBJECTIVES: In the present study, we aimed to investigate the possible involvement of the ACC dopamine D1 and D2 receptors in nicotine plus morphine-induced analgesia. METHODS: The ACC's of adult male Wistar rats were bilaterally cannulated by stereotaxic instrument and the tail-flick test was used to measure the thermal pain threshold. RESULTS: The results indicated that subcutaneous (s.c.) injection of nicotine (0.3 mg/kg) potentiated the analgesic response of intraperitoneal (i.p.) administration of morphine (3 mg/kg). Systemic administration of the same doses of nicotine or morphine alone had no effect on tail-flick latency. Intra-ACC administration of apomorphine (0.3-0.9 µg/rat), the non-selective D1/D2 receptors agonist, plus ineffective doses of nicotine (0.1 mg/kg, s.c.) plus morphine (3 mg/kg, i.p) induced analgesia in rats. In addition, the analgesia induced with co-administration of nicotine and morphine was inhibited via intra-ACC administration of SCH23390 (0.5-1 µg/rat) or sulpiride (0.5-2 µg/rat), the selective antagonists of D1 or D2 receptors, respectively. The intra-ACC microinjection of the same doses of drugs alone had no effect on tail-flick latency. Cubic interpolation analysis also confirmed that activation or inactivation of the ACC D1 and D2 receptors by different doses of drugs can modulate the nicotine-morphine analgesic response. CONCLUSIONS: The findings suggest that the ACC has an important role in acute thermal pain perception and modulates the analgesia induced by nicotine plus morphine via dopaminergic receptors.

Ventral tegmental area serotonin 5-HT1A receptors and corticolimbic cFos/BDNF/GFAP signaling pathways mediate dextromethorphan/morphine anti-allodynia.

AIMS: The present study examined the role of ventral tegmental area (VTA) serotonergic 5HT1A receptors in dextromethorphan/morphine-induced anti-allodynia and the possible changes of corticolimbic cFos, brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP) following the treatments. MATERIALS AND METHODS: The VTA cannulation and the chronic constriction of the sciatic nerve were performed in male Wistar rats. Flexion withdrawal thresholds to mechanical stimulation in the hind-limb were determined using von Frey hairs. The expressions of cFos, BDNF, and GFAP were evaluated using the Western blotting technique. KEY FINDINGS: BDNF (in the hippocampus), and GFAP (in the targeted sites) levels were increased following neuropathic pain. Morphine administration induced an anti-allodynic effect with a decrease in the amygdala BDNF level. Dextromethorphan/morphine-induced anti-allodynia was accompanied by the decrease of hippocampus/amygdala/PFC GFAP and amygdala cFos expressions. The PFC BDNF expression level was increased in dextromethorphan/morphine-treated rats. Intra-VTA microinjection of (S)-WAY100135 (1 µg/rat), a selective 5-HT1A receptor antagonist, inhibited the anti-allodynic effect of dextromethorphan/morphine. This treatment increased the cFos level in the hippocampus and the amygdala while decreased the PFC level of cFos. The hippocampal BDNF expression was significantly increased, while the amygdala and the PFC expressions of BDNF were decreased under treatment. (S)-WAY100135 plus dextromethorphan/morphine increased the hippocampal/amygdala and PFC levels of GFAP. SIGNIFICANCE: These findings indicate that dextromethorphan could potentiate the analgesic effect of morphine via the implication of the VTA serotonin 5-HT1A receptors. It seems that the changes in the corticolimbic cFos/BDNF/GFAP signaling pathway may be involved in the observed anti-allodynic effect.

Analgesic and anti-inflammatory properties of hydroalcoholic extracts of Malva sylvestris, Carum carvi or Medicago sativa, and their combination in a rat model.

OBJECTIVE: The aim of this study was to evaluate the analgesic and anti-inflammatory effects of the hydroalcoholic extracts of Malva sylvestris flowers or Carum carvi and Medicago sativa seeds, alone and in combination, which have been used in traditional Iranian medicine. METHODS: Male Wistar rats were divided into 6 treatment groups: distilled water, sodium salicylate (SS), M. sylvestris extract (600 mg/kg), C. carvi extract (600 mg/kg), M. sativa extract (300 mg/kg) and combined extract (including 300 mg/kg M. sylvestris and C. carvi extracts, and 150 mg/kg M. sativa extract). The formalin pain model was used to evaluate the antinociceptive effects of the treatments. For anti-inflammatory effect, acute (one hour after injection) and chronic (during a week after injection) paw inflammation was measured after subcutaneous injection of 2.5% formalin in the hindpaw. Finally, tissue samples from all groups were prepared for histopathological studies. RESULTS: The combined extract significantly inhibited the nociception in the acute phase of the formalin test (P < 0.001). In the chronic phase, all the extracts and SS had significant analgesic effect (P < 0.001). Analgesic activity of the combined extract was significantly stronger than SS (P < 0.01). In the acute inflammation model, M. sylvestris, C. carvi and the combined drug had significant inhibitory effects against paw edema (P < 0.05). All extracts, individually and in combination, significantly alleviated chronic paw inflammation (P < 0.01). The combined extract had much more anti-inflammatory activity than SS (P < 0.05). Histopathological results indicated improvement and reduction of inflammatory factors in the treatment groups. CONCLUSION: M. sylvestris, C. carvi and M. sativa have analgesic and anti-inflammatory properties. Potentially, each of these extracts or a mixture of them might be a valuable alternative drug to control pain and inflammation.

The blockade of 5-HT1A receptors in the ventral tegmental area inhibited morphine/dextromethorphan-induced analgesia in pain rat models.

The aim of the present study was to determine the involvement of the VTA 5-HT1A receptors in analgesia induced by the co-administration of morphine and dextromethorphan (DM). Male Wistar rats were bilaterally cannulated in the VTA by the stereotaxic instrument. The tail-flick and formalin tests were performed to assess nociception in the acute and tonic pain conditions respectively. The present data indicated that intraperitoneal (i.p.) administration of morphine increased the tail-flick latency (1-4 mg/kg) and decreased the pain score of formalin test (2-8 mg/kg), showing an analgesic effect. Co-administration of ineffective doses of morphine (1 or 2 mg/kg) with DM (30 mg/kg, i.p.) induced analgesia in both animal models. Interestingly, intra-VTA microinjection of 5HT1A receptors antagonist, S-WAY100-135 (0.5 and 1 µg/kg), inhibited the analgesic effect of morphine plus DM in both acute and tonic pain models. It should be considered that the same doses of DM or S-WAY100-135 by itself had no effects on antinociception in the animal models. Overall, these results indicated that systemic blockade of NMDA receptors via DM administration potentiated the response of a low dose of morphine to induce analgesic effect. Additionally, it seems that the VTA serotonergic system via 5HT1A receptors mediates the potentiative effect of DM on morphine-induced analgesia.