3. Umbruch 4.4..2005 - Online Pot

Cannabinoid targets for pain therapeutics 151
administered cannabinoids [20, 38], suggesting substantial contribution sites
in the brain. Hence it is possible that maximal analgesic effects could be difficult
to attain without penetration into brain sites, either by selective routes of
administration or with drugs that cannot penetrate the blood–brain barrier.
However, the real measure of clinical success often lies in balancing the degree
of pain relief with the extent of the unwanted side effects, which for cannabinoids
are mainly due to actions in the brain leading to undesirable psychotropic
effects.
Spinal action of cannabinoid agonists
Anti-nociceptive effects of cannabinoids are mediated in part at the spinal level,
as inhibition of spinal reflexive responses to noxious stimuli was observed in
spinally transected dogs [39]. Support for spinal mechanisms of cannabinoid
analgesic action is also found in studies that demonstrated analgesia following
intrathecal injections [40–42]. The behavioral data are consistent with the ability
of spinally administered cannabinoids to suppress noxious heat-evoked and
afterdischarge firing [19] and noxious stimulus-evoked Fos protein expression
in spinal dorsal horn neurons [27]. Spinal administration of a CB 1R agonist also
inhibits C-fiber- and A-δ-fiber evoked responses of spinal nociceptive neurons
in a CB 1-dependent mechanism [24]. Systemic and intrathecally administered
cannabinoids retain a weak but long-lasting anti-nociceptive effect in spinally
transected rats [38, 40], providing compelling evidence for spinal mechanisms
of cannabinoid anti-nociception.
Spinal administration of the ultra-potent cannabinoid HU-210 suppresses
C-fiber-mediated neuronal hyperexcitability in carrageenan-inflamed and
non-inflamed rats [23]; these effects were blocked by a CB 1R antagonist.
Similar to the results with HU-210, spinal administration of anandamide also
produced CB 1R-mediated effects in carrageenan-inflamed rats, but inconsistent
effects were observed in non-inflamed rats [43]. Although not established
following inflammation, upregulation of CB 1Rs is observed in the spinal cord
following nerve injury, suggesting that regulation of spinal CB 1Rs may contribute
to the therapeutic efficacy of cannabinoids in pathological pain states
[44]. The observation that cannabinoids act spinally to inhibit pain implies that
epidural cannabinoids may be effective in treating certain types of pain.
Peripheral action of cannabinoid agonists
Richardson and colleagues observed that peripheral administration of the
cannabinoid agonist anandamide suppressed thermal hyperalgesia and edema
in the carrageenan model of inflammation in a CB 1R-dependent manner [45].
The same dose administered to the non-inflamed contralateral paw was inactive,
indicating that the compound did not produce its effects by absorption