In mouse the cannabinoid receptor 2 (CB2) agonists L768242 and (+)-AM1241, at doses of 30 mg/kg i.p. and 1 and 3 mg/kg i.v., respectively, reduced the second phase of nocifensive behaviors elicited by formalin intraplantar injection. This effect was counteracted by the selective CB2 antagonist SR144528 (1 mg/kg i.p.). In rat (+)-AM1241 (3 and 6 mg/kg i.v.) and L768242 (30 mg/kg i.p.) reduced allodynia elicited by L5-L6 spinal nerve ligation. SR144528 reverted these effects, supporting a CB2-mediated action. To clarify the mechanisms underlying these effects we investigated CB2 gene expression and function in the nervous system. CB2 mRNA was expressed in spinal cord and dorsal root ganglia (DRG) of both sham and neuropathic rats and was up-regulated in the ipsilateral spinal cord of neuropathic rats. Expression studies demonstrated the presence of CB2 mRNA in culture of spinal cord microglia. A biomarker, CGRP, was used to investigate modulation of DRG primary afferents by CB2 agonists. Both L768242 and (+)-AM1241 dose dependently (EC50 of 3.6 and 4.5 nM, respectively) reduced capsaicin-induced calcitonin gene-related peptide (CGRP) release. Coadministration of SR144528 resulted in a rightforward shift (pKB 8.1 and 8.2 for (+)-AM1241 and L768242, respectively) of the dose-response curve. Experiments on capsaicin-induced CGRP release in tissue from CB1-/- mice ruled out a CB1-mediated effect. These results confirm that CB2 is present in the central nervous system and suggest that CB2 agonists may elicit their analgesic effect by acting not only at non-neuronal peripheral sites but also at neural level, making CB2 an attractive target for chronic pain treatment.

Both mGluR5 and mGluR1 antagonists are effective in models of pain and anxiety. However, an mGluR1 antagonist was more efficacious than the two mGluR5 antagonists in the pain models, which, conversely, appeared more efficacious in the anxiety models. These findings support the potential utility of mGluR5 and mGluR1 antagonists for both the treatment of chronic pain and as novel anxiolytics.

The adenosine A 2A receptor has been implicated in the underlying biology of various neurological and psychiatric disorders, including Parkinson's disease (PD) and depression. Preladenant and SCH 412348 [7-[2-[4-2,4- ,2,4]triazolo [1,5-c]pyrimidin-5-amine] are potent competitive antagonists of the human A 2A receptor (K i ϭ 1.1 and 0.6 nM, respectively) and have Ͼ1000-fold selectivity over all other adenosine receptors, making these compounds the most selective A 2A receptor antagonists reported to date. Both compounds attenuate hypolocomotion induced by the A 2A receptor agonist CGS-21680 [2-[p-(2-carboxyethyl)phenethylamino]-5Ј-N-ethylcarboxamidoadenosine], suggesting that they inhibit A 2A receptor activity in vivo. Their high degree of selectivity and robust in vivo activity make preladenant and SCH 412348 useful tools to investigate the role of the A 2A receptor system in animal models of PD and depression. Oral administration of preladenant and SCH 412348 (0.1-1 mg/kg) to rats potentiated 3,4-dihydroxy-L-phenylalanine (L-Dopa)-induced contralateral rotations after 6-hydroxydopamine lesions in the medial forebrain bundle and potently attenuated the cataleptic effects of haloperidol. Preladenant (1 mg/kg) inhibited L-Dopa-induced behavioral sensitization after repeated daily administration, which suggests a reduced risk of the development of dyskinesias. Finally, preladenant and SCH 412348 exhibited antidepressant-like profiles in models of behavioral despair, namely the mouse tail suspension test and the mouse and rat forced swim test. These studies demonstrate that preladenant and SCH 412348 are potent and selective A 2A receptor antagonists and provide further evidence of the potential therapeutic benefits of A 2A receptor inhibition in PD (with reduced risk of dyskinesias) and depression (one of the primary nonmotor symptoms of PD).Adenosine modulates neuronal function via its interaction with glutamatergic, cholinergic, GABAergic, and dopaminergic neurotransmitter systems (Kurokawa et al

To investigate the role of A 2A adenosine receptors in adaptive responses to chronic intermittent dopamine receptor stimulation, we compared the behavioral sensitization elicited by repeated L-DOPA treatment in hemiparkinsonian wild-type (WT) and A 2A adenosine receptor knock-out (A 2A KO) mice. Although the unilateral nigrostriatal lesion produced by intrastriatal injection of 6-hydroxydopamine was indistinguishable between WT and A 2A KO mice, they developed strikingly different patterns of behavioral sensitization after daily treatment with low doses of L-DOPA for 3 weeks. WT mice initially displayed modest contralateral rotational responses and then developed progressively greater responses that reached a maximum within 1 week and persisted for the duration of the treatment. In contrast, any rotational behavioral sensitization in A 2A KO mice was transient and completely reversed within 2 weeks. Similarly, the time to reach the peak rotation was progressively shortened in WT mice but remained unchanged in A 2A KO mice. Furthermore, daily L-DOPA treatment produced gradually sensitized grooming in WT mice but failed to induce any sensitized grooming in A 2A KO mice. Finally, repeated L-DOPA treatment reversed the 6-OHDA-induced reduction of striatal dynorphin mRNA in WT but not A 2A KO mice, raising the possibility that the A 2A receptor may contribute to L-DOPA-induced behavioral sensitization by facilitating adaptations within the dynorphinexpressing striatonigral pathway. Together these results demonstrate that the A 2A receptor plays a critical role in the development and particularly the persistence of behavioral sensitization to repeated L-DOPA treatment. Furthermore, they raise the possibility that the maladaptive dyskinetic responses to chronic L-DOPA treatment in Parkinson's disease may be attenuated by A 2A receptor inactivation. Key words: A 2A adenosine receptor; L-DOPA; behavioral sensitization; Parkinson's disease; dyskinesia; dynorphinFor Ͼ30 years the dopamine precursor L-DOPA has been the most effective and commonly prescribed treatment for Parkinson's disease (PD). Despite its considerable symptomatic motor benefit, chronic administration of L-DOPA leads to abnormal motor responses known as dyskinesias, involving involuntary choreic or dystonic movements in Ͼ50% of patients (5 years after the initiation of the treatment) (Chase, 1998;Obeso et al., 2000). Such shortcomings of L-DOPA and other dopaminergic drugs have prompted a search for alternative treatment strategies that provide symptomatic benefits while avoiding the delayed motor complications associated with the long-term use of antiparkinsonian drugs. Several neurotransmitters have been implicated in the motor complications elicited by repeated dopamine receptor stimulation, including glutamate (Marin et al., 1996;Tzschentke and Schmidt, 1998;Calabresi et al., 2000), cannabinoids (Souilhac et al., 1995;Zeng et al., 1999), opioids (Henry and Brotchie, 1996), and adenosine (Richardson et al., 1997;Kanda et al., 2000;Jenner, 2000). Recent...

No abstract

No abstract

No abstract

No abstract