CB1 expression in DRGs
-
Upload
yuli-carpenter -
Category
Documents
-
view
38 -
download
2
description
Transcript of CB1 expression in DRGs
CB1 expression in DRGs
NF200 IB4
CGRP
(Bridges et al 2003)
CB1 in redOther markers in greenColocalization in yellow
Control
NF200 IB4
CGRP
(Bridges et al 2003)
CB1 in redOther markers in greenColocalization in yellow
Control
Pharmacological tools
Selectivity and affinity of CB1 agonists are suboptimal
(Pertwee 2009)
CB1-mediated nociception
Sensory neurons specific CB1 KO
(Agarwal et al 2007)
DRG Spinal cord
(Agarwal et al 2007)
Expression in DRG Expression in brain
CB1-mediated nociceptionSensory neurons specific CB1 KO
CB1-mediated nociception
(Agarwal et al 2007)
Nociceptive response (acute pain) and locomotor performance
CB1-mediated nociception
(Agarwal et al 2007)
Nociceptive response (inflammatory pain)
CB1-mediated nociception
(Agarwal et al 2007)
Effect of WIN55212-2 on inflammatory pain
CB1-mediated nociception
(Agarwal et al 2007)
Effect of intrathecal vs intraplantar administration of WIN55212-2
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
CB2-mediated nociception
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)
CB2-mediated nociception
(Hanuš et al 1999)
CB2-mediated nociception
Effect on neuropathic pain
(Ibrahim et al. 2003)
AM1241
CB2-mediated nociception
(Ibrahim et al. 2003)
Sham-operated wt Spinal nerve ligated wt
Spinal nerve ligated CB1 KOSham-operated CB1 KO
Effect on neuropathic pain
Effect on neuropathic pain
CB2-mediated nociception
(Beltramo et al. 2006)
Reduction of mechanical allodynia in SNL rat
CB2-mediated nociception:cellular mechanisms
(Ibrahim et al. 2006)Release from paw skin
AM1241 antihyperalgesic effect in μ-opiod receptor wt and KO mice
CB2 localization
(Zhang et al 2003)
Expression in spinal cord
CB2 localization
Contralateral
CB2 in situ hybridization in the dorsal horn
Ipsilateral
CB2 CB2 OX42
(Zhang et al. 2003)
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