1. CB1 expression in DRGs

2. Pharmacological tools Selectivity and affinity of CB1 agonists are suboptimal (Pertwee 2009)

3. CB1-mediated nociception Sensory neurons specific CB1 KO (Agarwal et al 2007) DRG Spinal cord

4. (Agarwal et al 2007) Expression in DRG Expression in brain CB1-mediated nociception Sensory neurons specific CB1 KO

5. CB1-mediated nociception (Agarwal et al 2007) Nociceptive response (acute pain) and locomotor performance

6. CB1-mediated nociception (Agarwal et al 2007) Nociceptive response (inflammatory pain)

7. CB1-mediated nociception (Agarwal et al 2007) Effect of WIN55212-2 on inflammatory pain

8. CB1-mediated nociception (Agarwal et al 2007) Effect of intrathecal vs intraplantar administration of WIN55212-2

9. CB1-induced nociception: mechanism of action Two potential sites of action: –DRG: nociception –CNS: processing of nociceptive information Action on DRG blocks pain transmission to the CNS Action on the CNS may modulate nociceptive input elaboration

10. CB2-mediated nociception

11. CB2 synthetic agonists (Beltramo 2009) Bicyclic cannabinoid: HU308 (1) Cannabinor (2) THC derivatives: JWH133 (3) Aminoalkylindoles: AM1241 (4) L768242 (5) A-796260 (6) Pyrimidine derivatives: GW842166X (7) Thiazole derivatives: A-836339 (8) Carboxiamide derivatives: Taisho (9) Thiazine derivatives: Shonogi (10)

12. CB2-mediated nociception (Hanuš et al 1999)

13. CB2-mediated nociception Effect on neuropathic pain (Ibrahim et al. 2003) AM1241

14. CB2-mediated nociception (Ibrahim et al. 2003) Sham-operated wtSpinal nerve ligated wt Spinal nerve ligated CB1 KO Sham-operated CB1 KO Effect on neuropathic pain

15. CB2-mediated nociception (Beltramo et al. 2006) Reduction of mechanical allodynia in SNL rat

16. CB2-mediated nociception: cellular mechanisms (Ibrahim et al. 2006)Release from paw skin AM1241 antihyperalgesic effect in μ-opiod receptor wt and KO mice

17. CB2 localization (Zhang et al 2003) Expression in spinal cord

18. CB2 localization Contralateral CB2 in situ hybridization in the dorsal horn Ipsilateral CB2 OX42 (Zhang et al. 2003)

19. Summary and perspectives The cannabinoid system play an important role in nociception The research to develop a cannabinoid analgesic has made significant progress CB2 agonist and mixed peripherally restricted agonists are at present the most promising strategies Research on the inactivation system is progressing and show interesting potential Side effects and regulatory constrain remain important issues to be solved