510 J.M. Walker and A.G. Hohmann
5.1.2EffectsofInhibitionofthePutativeAnandamideTransporter ......... 533
5.1.3ModulationofPainbyEndogenousAnandamide................ 534
5.2 Dihomo-γ-LinolenoylethanolamideandDocosatetraenylethanolamide.... 534
5.3 2-Arachidonoylglycerol.............................. 535
5.4 NoladinEther ................................... 535
5.5 Virodhamine.................................... 536
5.6 N-Arachidonoyldopamine ............................ 536
5.7 RegulationofEndocannabinoidsbyFattyAcidAmideHydrolase ....... 536
5.7.1PainSensitivityandInflammatoryResponsesinFAAHKnockoutMice.... 537
5.8 Role of Endocannabinoids in the Antinociceptive Actions
ofCyclooxygenaseInhibitors........................... 538
5.9 Evidence for Tonic Modulation of Pain via CB1Rs................ 538
5.9.1 Pain Sensitivity in CB1R Knockout Mice. .................... 538
5.9.2EffectsofEndocannabinoidsAssessedwithCBRantagonists.......... 539
6 Effects of Cannabinoids on Pain in Humans................... 539
6.1 ExperimentalPain................................. 540
6.2 ClinicalPain.................................... 542
7Conclusions.................................... 543
References ........................................ 543
AbstractA large body of literature indicates that cannabinoids suppress behav-
ioral responses to acute and persistent noxious stimulation in animals. This review
examines neuroanatomical, behavioral, and neurophysiological evidence support-
ing a role for cannabinoids in suppressing pain at spinal, supraspinal, and pe-
ripheral levels. Localization studies employing receptor binding and quantitative
autoradiography, immunocytochemistry, and in situ hybridization are reviewed
to examine the distribution of cannabinoid receptors at these levels and provide
a neuroanatomical framework with which to understand the roles of endogenous
cannabinoids in sensory processing. Pharmacological and transgenic approaches
that have been used to study cannabinoid antinociceptive mechanisms are de-
scribed. These studies provide insight into the functional roles of cannabinoid
CB 1 (CB1R) and CB 2 (CB2R) receptor subtypes in cannabinoid antinociceptive
mechanisms, as revealed in animal models of acute and persistent pain. The role of
endocannabinoids and related fatty acid amides that are implicated in endogenous
mechanisms for pain suppression are discussed. Human studies evaluating ther-
apeutic potential of cannabinoid pharmacotherapies in experimental and clinical
pain syndromes are evaluated. The potential of exploiting cannabinoid antinoci-
ceptive mechanisms in novel pharmacotherapies for pain is discussed.
KeywordsEndocannabinoid · Spinal cord · Periaqueductal gray · Supraspinal ·
Peripheral · CB1 · CB2 · THC · Hyperalgesia · Clinical pain
The study of the role of endocannabinoids in pain is founded in research on pain
mechanisms, a vital field that is steadily evolving on many fronts. A brief overview
of the current thinking on the neural basis of pain is thus provided as background