Activation of CB ₂ cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: Pain inhibition by receptors not present in the CNS

Abstract

We designed AM1241, a selective CB2 cannabinoid receptor agonist, and used it to test the hypothesis that CB2 receptor activation would reverse the sensory hypersensitivity observed in neuropathic pain states. AM1241 exhibits high affinity and selectivity for CB 2 receptors. It also exhibits high potency in vivo. AM1241 dose-dependently reversed tactile and thermal hypersensitivity produced by ligation of the L5 and L6 spinal nerves in rats. These effects were selectively antagonized by a CB 2 but not by a CB1 receptor antagonist, suggesting that they were produced by actions of AM1241 at CB 2 receptors. AM1241 was also active in blocking spinal nerve ligation-induced tactile and thermal hypersensitivity in mice lacking CB 1 receptors (CB1 ؊/؊ mice), confirming that AM1241 reverses sensory hypersensitivity independent of actions at CB 1 receptors. These findings demonstrate a mechanism leading to the inhibition of pain, one that targets receptors localized exclusively outside the CNS. Further, they suggest the potential use of CB 2 receptor-selective agonists for treatment of human neuropathic pain, a condition currently without consistently effective therapies. CB 2 receptor-selective agonist medications are predicted to be without the CNS side effects that limit the effectiveness of currently available medications. N europathic pain is defined as pain initiated or caused by a primary lesion or dysfunction in the nervous system (1). It affects Ϸ1% of the population and results from a variety of etiologies including trauma, infection, diabetes, immune deficiencies, ischemic disorders, and toxic neuropathies (1, 2). It can be excruciating, and some patients are unable to work or to perform normal daily activities. Neuropathic pain often responds poorly to medical therapy (3,4). This may be due, in part, to adverse side effects of available medications that limit drug dosage (5). Medications currently used for the treatment of neuropathic pain act on neurotransmitter systems or ion channels and typically produce significant CNS side effects. For example, gabapentin, a drug commonly used to treat neuropathic pain because of its modest side effect profile compared with other therapeutic options, produces somnolence in 19% of patients and dizziness in 17% (Neurontin prescribing information, Parke-Davis). A therapy directed at targets not found in the CNS would avoid these problems. CB 2 cannabinoid receptors are one such potential target.CB 2 receptor mRNA is not detected in brain (6, 7). In addition, the CB 2 receptor-selective antagonist SR144528 did not displace the nonselective cannabinoid ligand [ 3 H]CP55,940 from binding to rat brain (7). Finally, binding of [ 3 H]CP55,940 to mouse brain was eliminated by disruption of the CB 1 receptor gene (8) but was not affected by disruption of the CB 2 receptor gene (9). These studies suggest that CB 2 receptors are not found in the normal CNS, although they do not fully exclude the possibility that CB 2 receptors are expressed in the CNS in small, but functionally signi...

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