Pernia -Andrade et al. (2009) Science 325:760-764.

1. Spinal Endocannabinoids and CB1Receptors Mediate C-Fiber–InducedHeterosynaptic Pain Sensitization Pernia-Andrade et al. (2009) Science 325:760-764.

2. What are cannabinoids? • Lipid neurotransmitters that are synthesized on demand (activity-dependent) and require an active transport molecule (?) to move across the synaptic cleft. • Endocannabinoids = endogenous cannabinoids • 2-arachydonoyl glycerol (2AG) and anandamide (AEA) are the most prevalent endocannabinoids • Receptors • CB1 and CB2, both G protein-coupled receptors • TRPV1 (transient receptor potential vanilloid 1), an ionotropic receptor that also responds to heat and H+ • GPR55, a third G protein-coupled receptor (still debated)

3. There is considerable interest in developing cannabiniod-based analgesics • This is largely motivated by problems with many of the opioid-based analgesics. • Potential for abuse (higher rates for death by overdose than some illegal drugs) • Depress respiration • Can initiate rebound hyperalgesia • Current cannabinoid-based treatments use analogs of endogenous cannabinoids transmitters (agonists) • e.g. marinol (synthetic THC) and cannabidiol • A better approach may be drugs that increase endocannabinoid levels (increase synthesis or transport, decrease metabolism).

4. Endocannabinoid signaling Guindon & Hohmann, 2009

5. Fig. 1. Synaptic effects of CB1 receptor activation in dorsal horn neuronal Pernia-Andrade et al. 2009

6. Paired-pulse Facilitation Presynaptic Action Potentials Postsynaptic EPSPs Red arrows indicate timing of presynaptic action potentials 1 sec

7. Fig. 2. Inhibition of glycinergicand GABAergic synaptic transmission via presynaptic CB1 receptors. Paired-pulse Coefficient of variation

8. Fig. 3. Extracellular single-unit recordings from deep dorsal horn neurons in intact rats.

9. Fig. 4. Effects of pharmacological and genetic manipulations of the endocannabinoid system on capsaicin-induced mechanical hyperalgesia in mice.

10. Fig. S8. Schematic representation of a neuronal model circuit of the spinal dorsal horn possibly underlying activity-dependent and endocannabinoid-mediated secondary hyperalgesia.