3. Umbruch 4.4..2005 - Online Pot

Cannabinoid targets for pain therapeutics 155
neuropathic or nerve-injury pain [44, 51, 73–80], sometimes with increased
potency compared to effects in naive animals.
Data from the clinical studies tend to agree with centuries of anecdotal data
showing the effectiveness of systemically administered cannabinoids against
clinical pain. However, the unfortunate fact is that for the compounds tested to
date, maximal analgesia could not be obtained from systemic administration of
direct-acting CB 1 cannabinoid agonists at doses that do not elicit psychotropic
effects. While typical cannabinoids are relatively safe (no deaths linked to
overdose) and do not appear to have serious toxicity problems, psychotropic
effects have limited the dosing, preventing cannabinoid agonists from reaching
their full potential for use in the clinic. More work on developing agonists
that lack psychotropic side effects would be beneficial, and may be fruitful
based upon recent studies described below.
Development of non-psychotropic cannabinoids
One possible strategy that has emerged from the study of the cannabinoid system
at the cellular and molecular level is the exploitation of differential signal
transduction mechanisms that can be coupled to the cannabinoid receptor.
Several studies reported that a single cannabinoid agonist could elicit different
degrees of signal amplification across various regions of the brain [81, 82], and
the various types of G-protein subunits that exist throughout the brain were
activated to varying degrees [83]. Moreover, different cannabinoid agonists
were found to evoke different levels of activation of a single G protein subtype
[84, 85], and the G protein subtype selectivity is conferred by distinct intracellular
domains of the receptor [86]. Hence, it is conceivable that an agonist
could be developed that would activate cannabinoid receptors and signal transduction
pathways associated with pain suppression but not those associated
with psychotropic effects and motor dysfunction. This possibility is further
supported by the separation of neural circuits that mediate cannabinoid motor
dysfunction (basal ganglia, cerebellum) from those that mediate analgesia
(periaqueductal gray, rostral ventral medulla, spinal cord, peripheral nerve)
[87–89], as it allows for the compartmentalization of distinct G protein subtypes
and second messengers to particular regions of the brain, and hence
physiological functions. If the circuits mediating cannabinoid agonist-induced
pain-suppressive effects rely principally on second messengers different from
those responsible for psychotropic effects, then it may be possible to develop
drugs that preferentially activate these signalling mechanisms and achieve a
pain-suppression-specific cannabinoid agonist. Further investigation into this
avenue of drug development is necessary to determine its practical feasibility.
Examples of results from recent work aimed at developing cannabinoids
lacking psychotropic side effects are the ∆ 9 -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 [90–92],