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This study was undertaken to characterize further the central cannabinoid receptors in rat primary neuronal cell cultures from selected brain structures. By using [ 3H]SR141716A, the specific OB1 receptor antagonist, we demonstrate in cortical neurons the presence of a high density of specific binding sites (Brnax = 139 ± 9 fmol/mg of protein) displaying a high affinity (KD = 0.76 ± 0.09 nM). The two cannabinoid receptor agonists, OP 55940 and WIN 55212-2, inhibited in a concentrationdependent manner cyclic AMP production induced by either 1~M forskolin or isoproterenol with EC 50 values in the nanomolar range (4.6 and 65 nM with forskolin and 1.0 and 5.1 nM with isoproterenol for CP 55940 and WIN 55212-2, respectively). Moreover, in striatal neurons and cerebellar granule cells, OP 55940 was also able to reduce the cyclic AMP accumulation induced by 1 ,uM forskolin with a potency similar to that observed in cortical neurons (E050 values of 3.5 and 1.9 nM in striatum and cerebellum, respectively). SR 141716A antagonized the OP 55940-and WIN 55212-2-induced inhibition of cyclic AMP accumulation, suggesting CB1 receptor-specific mediation of these effects on all primary cultures tested. Furthermore, OP 55940 was unable to induce mitogenactivated protein kinase activation in either cortical or striatal neurons. In conclusion, our results show nanomolar efficiencies for OP 55940 and WIN 5521 2-2 on adenylyl cyclase activity and no effect on any other signal transduction pathway investigated in primary neuronal cultures.

Trigeminal stimulation of C-fibers increased c-fos expression within the trigeminal nucleus caudalis (NtV) and thalamic neuronal activity which both reflect the transmission of a nociceptive message. We examined the effects on both these phenomena of the selective NK1 and NK2 receptor antagonists, SR140333 and SR48968. SR140333 (0.3, 1 and 3 micrograms/kg intravenously [i.v.]) dose-dependently, reversibly and stereoselectively antagonized the increase of contralateral thalamic activity. This compound, when given i.v. (30 micrograms/kg) or orally (10 mg/kg), also reduced the number of Fos-like immunoreactive cells particularly at the medial and caudal level of the NtV. In contrast, SR48968 did not exert any antagonistic effect either on thalamic activity or on Fos-like immunoreactivity. The data strongly suggest a preferential involvement of NK1 vs NK2 receptors in nociceptive transmission following trigeminal ganglion stimulation. Taken together, our results indicate that SR140333 could provide a potent drug for the relief of pain occurring under excessive activity of sensory trigeminal fibers.