3. Umbruch 4.4..2005 - Online Pot

152 S.M. Huang and J.M. Walker
into the systemic circulation. This finding indicates that CB 1R agonists acting
in the periphery are sufficient to inhibit pain. Intraplantar administration of the
mixed CB 1/CB 2 agonist WIN-55,212-2 also attenuated the development of carrageenan-evoked
mechanical hyperalgesia, allodynia and spinal Fos protein
expression in a CB 1R- and CB 2R-dependent manner [30].
Effects of cannabinoid CB 2-specific agonists
CB 2Rs are either absent or expressed in low levels by neural tissues [7, 46] but
are present on immune cells and hence may have implications for pain. This
distribution has led to the evaluation and validation of the CB 2R as a target for
novel pharmacotherapies for pain, an attractive possibility because CB 2R agonists
lack psychotropic side effects.
CB 2R agonists are anti-nociceptive in models of acute [47] and persistent
[29, 48–51] pain. Hanusˇ and colleagues [49] demonstrated that the selective
CB 2 agonist HU-308 produced marked decreases in pain behavior in rats
receiving hindpaw injections of dilute formalin with no change in motor function,
a side effect often seen with CB 1R agonists which may predict psychoactivity
in humans. Another CB 2R agonist, AM-1241, has also been shown
to induce CB 2R-mediated analgesia in acute pain paradigms while failing to
elicit centrally mediated side effects such as hypothermia, catalepsy and
hypoactivity [47]. In inflammatory pain models, AM-1241 also induces
CB 2R-mediated suppression of carrageenan- and capsaicin-evoked thermal
and mechanical hyperalgesia and allodynia [30, 50, 52].
Substances released by immune cells such as histamine, serotonin
(5-hydroxytryptamine), eicosanoids, interleukin 1, tumor necrosis factor-α,
and nerve growth factor sensitize nociceptors [53–55]. Therefore, it is plausible
that activation of CB 2Rs on immune cells could suppress pain.
Cannabinoid agonists have been shown to inhibit the release of inflammatory
mediators from monocytic cells [56] and mast cells [57]. Direct effects on
CB 2Rs localized to primary afferents have been postulated [58–62], though the
basis for such effects is unclear in light of the paucity or lack of CB 2R expression
in neural tissues. It would appear from these findings that CB 2R selective
agonists are a promising target for drugs to treat pain and inflammation.
Effects of cannabinoid agonists in humans
The human trials of cannabis and ∆ 9 -THC are few in number and typically
small in subject size. There are marked differences between studies in dose
regimens and drug preparations, with some using smoked marijuana and others
using ∆ 9 -THC by oral or intravenous routes. Some studies used healthy
volunteers, whereas others used patients with clinical pain. Therefore, it is
important to note that: (1) some negative results may have arisen from admin-