Inhibition of pain responses by activation of CB₂ cannabinoid receptors

Cannabinoid receptor agonists diminish responses to painful stimuli. Extensive evidence demonstrates that CB₁ cannabinoid receptor activation inhibits pain responses. Recently, the synthesis of CB₂ cannabinoid receptor-selective agonists has allowed testing whether CB₂ receptor activation inhibits pain. CB₂ receptor activation is sufficient to inhibit acute nociception, inflammatory hyperalgesia, and the allodynia and hyperalgesia produced in a neuropathic pain model. Studies using site-specific administration of agonist and antagonist have suggested that CB₂ receptor agonists inhibit pain responses by acting at peripheral sites. CB₂ receptor activation also inhibits edema and plasma extravasation produced by inflammation. CB₂ receptor-selective agonists do not produce central nervous system (CNS) effects typical of cannabinoids retaining agonist activity at the CB₁ receptor. Peripheral antinociception without CNS effects is consistent with the peripheral distribution of CB₂ receptors. CB₂ receptor agonists may have promise for the treatment of pain and inflammation without CNS side effects.