3. Umbruch 4.4..2005 - Online Pot

150 S.M. Huang and J.M. Walker
the development of cannabinoid-based therapeutics for pain. Reviews covering
basic research on the physiological role of endogenous cannabinoids in pain
modulation can be found elsewhere [11].
Effects of direct-acting cannabinoid receptor agonists
Perhaps the earliest published preclinical experiment on the effects of cannabinoids
on pain was that conducted by Dixon [12], who showed that dogs that
inhaled cannabis smoke failed to react to pin pricks. After the isolation of
∆ 9 -THC, Bicher and Mechoulam [13] and Kosersky and colleagues [14]
demonstrated that this chemical component of cannabis profoundly suppressed
behavioral reactions to acute noxious stimuli and inflammatory pain. It was
noted early on that the potency and efficacy of cannabinoids in acute pain paradigms
rival that of morphine [15, 16]. However, cannabinoids also produce
profound motor effects such as immobility and catalepsy [17], which raised a
potential confounding factor for studies that assessed pain behavior, because
escape or withdrawal responses to noxious stimuli are integral to the assessment.
In part to address this potential confounding factor, experiments were
initiated to determine whether cannabinoids suppress the spinal and thalamic
circuits that give rise to pain sensations. These experiments demonstrated that
cannabinoids selectively suppress noxious stimulus-evoked neuronal activity
in spinal and thalamic nociceptive neurons [18–22]. This effect is observed
with all modalities of noxious stimulation tested (mechanical, thermal, chemical),
is mediated by cannabinoid receptors, and correlates with the pain-suppressive
behavioral effects of cannabinoids [18–21]. Cannabinoids suppress
C-fiber-evoked responses in spinal dorsal-horn neurons recorded in normal
and inflamed rats [22–24]. Spinal expression of Fos protein, a marker of sustained
neuronal activation [25], is also suppressed by cannabinoids in animal
models of persistent pain [26–31].
Brain action of cannabinoid agonists
Intracerebroventricular administration of systemically inactive doses cannabinoid
agonists suppresses pain with only miniscule amounts reaching the spinal
cord at the time of peak analgesia [32]. When administered in this fashion,
cannabinoids inhibit spinal nociceptive responses by actions on specific circuits
in the brain that serve naturally to modulate pain sensitivity. These areas
include the dorsolateral periaqueductal gray, dorsal raphe n., rostral ventral
medulla, amygdala, lateral posterior and submedius regions of the thalamus,
superior colliculus and noradrenergic nucleus A5 region [33–35]. It appears
that the descending noradrenergic system is important in mediating the effects
of cannabinoids in the brain [36, 37]. When spinal transection was performed
in rats, there was a marked attenuation of the analgesic effects of systemically