Cannabinoid Mechanisms of Pain Suppression 515fathers of modern pharmacology, Ernest Dixon (1899). He observed that dogs that
inhaled cannabis smoke failed to react to pin pricks. Early studies by Bicher and
Mechoulam (1968) and Kosersky et al. (1973) provided a foundation for subsequent
workthatverifiedtheabilityofcannabinoidstoprofoundlysuppressbehavioralre-
actions to acute noxious stimuli and inflammatory and nerve injury-induced pain.
In these early studies, it was noted that the potency and efficacy of cannabinoids
rival that of morphine (Bloom et al. 1977; Buxbaum 1972). However, cannabi-
noids also produce profound motor effects [e.g., immobility, catalepsy; (Martin et
al. 1991)], a potential confound for behavioral studies, which inevitably employ
motor responses to noxious stimuli as a measure of pain sensitivity.
In part to address this potential confound, subsequent electrophysiological
and neurochemical studies examined the question of whether cannabinoids sup-
press activity within pain circuits. These studies provided convincing evidence that
cannabinoids suppress nociceptive transmission in vivo (see Hohmann 2002 for re-
view). Walker’s laboratory first demonstrated that cannabinoids suppress noxious
stimulus-evoked neuronal activity in nociceptive neurons in the spinal cord (Fig. 2)
Fig.2.Exampleofinhibitionofnoxiousheat-evokedactivityinalumbardorsalhornneuronbythecannabinoid
WIN55,212-2. The responses of the neuron to a 50°C stimulus were examined during 16 stimulus trials.AThe
noxious stimulus, illustrated by the temperature waveform (topcenter), was administered at 2.5-min intervals.
Theblack peristimulus time histogramrepresents baseline firing prior to injection of the synthetic CB1R/CB2R
agonist WIN55,212-2 (125 μg/kg i.v.).Thegray peristimulus time histogramrepresents the firing rate for the
first five post-injection trials.BComparison of the mean firing rate during the stimulus for the five baseline
trials to the firing rate during the stimulus for the first five post-injection trials illustrating, approximately, a
75% decrease in responsiveness. (Redrawn from Hohmann et al. 1999b)