Cannabis: A journey from college to bench to bedside

Ken Mackie (IUB)

Michael Vasko (IUSM)

Pain therapies

• Inadequately-treated chronic pain is a major clinical problem

• Current behavioral and pharmacological approaches: limited efficacy

• Need for better therapies• Cannabinoids as novel pain therapeutics:

– Cannabinoids = active components of cannabis (e.g., THC)

Cannabinoids

• Analgesic efficacy similar to codeine• Actions fundamentally different from opiates• Cellular site of action > 2 receptors

– CB1 > well studied, analgesia, but psychoactivity

– CB2 > little studied, analgesia, no psychoactivity

• Therapeutic approaches:– Ligands to activate cannabinoid receptors– Enzyme inhibitors to increase endogenous ligands

(endocannabinoids)

Goals of our study (1)

• What does CB2 do in neurons?

– CB1 inhibits neurotransmitter release

– Will CB2 receptors do the same?

• CB2 is highly inducible– Therapeutically beneficial(?)– How to study function?

• Introduce into cultured neurons– Deliverable 1: Will CB2 inhibit

neurotransmission in vivo?

Maresz et al. J. Neurochem. 95 (2005) 437-45

Goals of our study (2)

• What is the in vivo role of CB2? – Deliverable 2: Develop lentiviral tools to over express

and knock down CB2 expression in sensory neurons

– Deliverable 3: Will over expression of CB2 decrease pain?

– Deliverable 4: Will knockdown of CB2 increase pain?

Will CB2 inhibit neurotransmission in vivo?

• Background:– CB1 receptors inhibit

neurotransmission

• Approach– Culture neurons from CB1 KO mice

– Express CB2 receptors in these neurons

– Examine neurotransmission• Exogenous cannabinoids• Endogenous cannabinoids

Bodor et al, 2005 (layer V)

Summary

• CB2 receptors in neurons can inhibit neurotransmission– Presynaptic site of action

• Tools have been made to over express and knockdown CB2 expression in vivo

• Next – test and demonstrate efficacy with in vivo models

Acknowledgements

• Funding: RR025761, DA021696, and DA011322

• LMIC• Brady Atwood