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LeadDiscovery Reports
Cannabinoid receptor ligands in the treament of pain
Approximately 9% of the US
population suffers from moderate to severe non-cancer-related pain, a figure
that includes 40-70 million individuals with chronic pain. This condition
precipitates other serious pathologies such as depression and is associated
with an estimated pharmaceuticals market of US$18.7 billion worldwide.
Neuropathic pain is associated with a variety of etiologies including trauma,
infection, diabetes, immune deficiencies, ischemic disorders, and toxic
neuropathies. Approximately 26 million patients are affected worldwide and the
lifestyle of this cohort can be severely impeded, a problem compounded by the
lack of efficacy and frequent incidence of side effects associated with
current treatment options.
Exogenous cannabinoids are effective in attenuating neuropathic pain behaviors
induced by peripheral nerve injury. Cannabinoids and their derivatives exert
their effects via "central" CB1 receptors, mostly expressed in brain and
responsible for cannabinoid psychoactivity, and "peripheral" CB2 receptors,
mostly expressed in the immune system and unrelated to cannabinoid
psychoactivity. In our previous edition of TherapeuticAdvances we highlighted
a publication by Ibrahim et al describing the use of CB2 agonists as a new
approach to neuropathic pain.
In this edition we focus on the mechanism underlying the efficacy of CB1
receptor agonists in the treatment of neuropathic pain. In their recent paper,
Lim et al report the expression of spinal CB1 receptors following chronic
constriction sciatic nerve injury and its relation to the effects of a
cannabinoid receptor agonist (Win 55,212-2) on neuropathic pain in rats. Nerve
injury upregulated spinal CB1 receptor expression via a tyrosine kinase
receptor-mediated mechanism, primarily within the ipsilateral superficial
spinal cord dorsal horn. Although overexpression did not contribute to the
development of neuropathic pain, it did facilitate an enhanced effect of Win
55,212-2 on both thermal hyperalgesia and mechanical allodynia. This contrasts
with opioids that become less effective in neuropathic pain models.
This study supports the development of CB1 agonists for the treatment of
neuropathic pain. Furthermore, if during the neuropathic state the response of
pain pathways to cannabinoid increases while cannabinoid-related psychoactive
side effects remain constant the therapeutic window of CB1 agonists may widen.
This is an important consideration both with respect to the efficacy of
cannabinoid receptor agonists and also to conclusions that are drawn from dose
finding clinical studies.
Entry date Monday, November 10, 2003
Adapted from Lim et al, Pain. 2003 Sep;105(1-2):275-283.
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