Spinal Endocannabinoids and CB1

Receptors Mediate C-Fiber–InducedHeterosynaptic 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– 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)

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 CB1 receptor activation in dorsal horn neuronal

Pernia-Andrade et al. 2009

Paired-pulse Facilitation

1 sec

Postsynaptic EPSPs

Red arrows indicate timing of presynaptic

action potentials

Presynaptic Action Potentials

Fig. 2. Inhibition of glycinergic and GABAergic synaptic transmission via presynaptic CB1 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.