Spinal Endocannabinoids and CB

1

Receptors Mediate C-Fiber–Induced Heterosynaptic Pain Sensitization Pernia-Andrade et al. (2009) Science 325:760-764.

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)

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).

Endocannabinoid signaling

Guindon & Hohmann, 2009

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

Presynaptic Action Potentials

Paired-pulse Facilitation

Postsynaptic EPSPs Red arrows indicate timing of presynaptic action potentials 1 sec

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

Paired-pulse Coefficient of variation

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

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

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