1. Spinal Endocannabinoids and CB 1 Receptors Mediate C-Fiber–Induced Heterosynaptic 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 – CB 1 and CB 2, both G protein-coupled receptors – TRPV 1 (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 CB 1 receptor activation in dorsal horn neuronal Pernia-Andrade et al. 2009

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

7. Fig. 2. Inhibition of glycinergic and GABAergic synaptic transmission via presynaptic CB 1 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.