Cannabinoid Mechanisms of Pain Suppression 543man immunodeficiency virus (HIV) RNA levels, CD4+and CD8+cell counts, or
protease inhibitor levels] in individuals with HIV infection (Abrams et al. 2003).
Cannabinoids also represent a promising therapeutic target in acquired immun-
odeficiency syndrome (AIDS) and cancer patients where the antiemetic effects
of cannabinoids represent a useful therapeutic adjunct in patient populations for
whom the emetic effects of opioids are poorly tolerated.
Recent work has aimed at developing cannabinoids that lack psychotropic side
effects, which limit dosing. One example of this may be found in the THC and
cannabidiol acid derivatives ajulemic acid (CT-3) and HU-320. These compounds
were reported to produce anti-inflammatory effects with a reduced side effect
profile (Burstein et al. 1998; Burstein et al. 2004; Sumariwalla et al. 2004), perhaps
because they possess either poor (ajulemic acid) or virtually no (HU-320) affinity
for either CB1R or CB2R. Consequently, the mechanism by which they produce
analgesic effects is not clear. In a recent clinical trial of patients suffering from
neuropathic pain, ajulemic acid possessed some efficacy (Karst et al. 2003). While
many questions about these and similar compounds are awaiting further research,
this appears to be an important line of inquiry.
7
Conclusions
Although cannabinoids have been used for pain relief for centuries, the basis for
theiranalgesiceffectswerepoorlyunderstooduntilrecently.Duringthelastdecade
a prodigious output of research papers from many laboratories has elucidated
many of the major features of cannabinoid analgesia. These studies have not only
provided a detailed understanding of the network of neural and inflammatory cells
that serve as the targets of cannabinoids, the literature has also begun to address
the more difficult question of the physiological role of endocannabinoids in pain
regulatory circuits. The low levels of CBRs in brainstem regions that control vital
heartrateandrespiratoryfunctionprovidedananatomicalbasisforthelowtoxicity
of cannabinoids (Herkenham et al. 1991). However, the psychoactivity of direct-
acting CB1R agonists proved to be a major barrier to their use as therapeutic
tools in the pharmacotherapy of chronic pain. More encouraging results have
arisen from a number of studies showing positive effects of CB2R agonists, locally
administered cannabinoids, inhibitors of the anandamide-degrading enzyme or
the putative anandamide transporter, or the use of atypical cannabinoids such as
HU-320. Such novel targets for pain pharmacotherapy represent important future
directions for research in this field.
References
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Kosel B, Aberg JA, Deeks SG, Mitchell TF, Mulligan K, Bacchetti P, McCune JM, Scham-
belan M (2003) Short-term effects of cannabinoids in patients with HIV-1 infection:
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