Focus On: Neuropathic Pain and Appraising Drug SafetyNovel targets in pain research: The case for CB2 receptors as a biorational pain target
Section snippets
Introduction: neuropathic pain
Neuropathic pain arises from damage to peripheral or central nerve pathways which results in a persistent state of spontaneous pain and/or hypersensitivity to painful and innocuous stimuli, and can be mirrored bilaterally where no actual nerve damage exists. The underlying aetiologies of neuropathic pain vary considerably, but often present with similar clinical hallmarks. Some of the most common pathologies resulting in neuropathic pain are diabetic neuropathy, amputation or surgical
Current treatments for neuropathic pain
Neuropathic pain is difficult to treat for a number of reasons. Diverse, often idiopathic, aetiologies mean intervention is often limited to treatment of symptoms. Limited efficacy, pharmacoresistance, and adverse side effects, all contribute to poor pharmacological management of neuropathic pain. Gabapentin, pregabalin, and tricyclic antidepressants (TCAs) are considered first line treatments for most cases of neuropathic pain. Other treatments are targeted at specific neuropathies. For
Effectiveness of current cannabinoids in treating neuropathic pain
Clinical trials have shown Δ9-THC, and some of its analogues are moderately effective at reducing neuropathic pain. Iskedjian et al.5 analysed data from six published studies combined with additional unpublished trial data provided by GW Pharmaceuticals (the producers of the cannabis-based drug, Sativex). Sativex decreased pain by 1.7 ± 0.7 points (p = 0.018) on an 11-point scale; the non-psychoactive cannabidiol by 1.5 ± 0.7 points (p = 0.044); and the synthetic isomer of Δ9-THC, dronabinol, by 1.5 ±
Limitations of cannabinoids for treating neuropathic pain in clinical trial
The cannabinoids that have been used in clinical trial are psychoactive, causing drowsiness, ataxia, dizziness, and confusion. This severely limits the dose that can be used for the treatment of neuropathic pain, and the dose that patients will accept in clinical trials is limited by these effects. Patients tended to gradually titrate their dose to an acceptable level of intoxication whilst retaining pain-relieving effects. The key challenge for the development of improved cannabinoid drug
The endocannabinoid system: a target for treating neuropathic pain
Cannabinoids exert their effects via a group of Gi/o-linked seven trans-membrane domain G protein-coupled receptors (GPCRs), collectively known as cannabinoid receptors (CBRs).6 In the mammalian CNS, the cannabinoid CB1 receptor is expressed at high densities in the substantia nigra, globus pallidus, cerebellum, hippocampus, cerebral cortex, and striatum, but at relatively low densities in the brainstem and thalamus. Expression of CB1 has also been reported in human tonsils, spleen, ovaries,
Strategies for the development of cannabinoid analgesia
The majority of the psychoactive effects of cannabinoids are mediated through CB1 receptors in the brain, and the challenge for improving cannabinoid treatment of neuropathic pain is to target the endocannabinoid system in the pain pathway with minimal activation of brain CB1 receptors. There are a number of ways that this may be achieved. One promising strategy is to target CB2 receptors with selective CB2 agonists.
CB2 agonists for neuropathic pain: preclinical evidence
A number of synthetic CB2 ligands have been found to reduce neuropathic pain in rodent models (see Table 1 for specific references for this section). AM1241, a high-affinity and high-potency CB2 agonist, alleviated mechanical and thermal hyperalgesia in the Chung Spinal Nerve Ligation (SNL) model via a CB1-independent and CB2-dependent mechanism. AM1241 has also been found to alleviate chemotherapy-induced mechanical allodynia, with the effect attenuated by CB2 but not CB1 antagonists. Using
CB2 receptor agonists and psychoactive effects
CB2 agonists do not cause the classical behavioural effects of Δ9-THC when administered at doses that are specific for CB2,10 consistent with experiments that have shown that there are few, if any, neuronal CB2 agonist binding sites in the healthy brain. Although recent studies have suggested that CB2 expression may be induced in neurons in the injured CNS,11 with highly specific exceptions, CB2 does not appear to be expressed in mature brain neurons in the healthy brain. In situ hybridization
CB2 receptor agonists
Because of their potential to provide analgesia without undesirable CB1-mediated side effects, there has been considerable interest in developing selective CB2 receptor agonists. The first cannabinoid to have its chemical structure characterised was cannabinol, isolated from nearly 70 terpenophenols identified as constituents of Cannabis sativa. This was followed by characterisation of the psychoactive compound Δ9-tetrahydrocannabinol (Δ9-THC), which is responsible for most of the
Mechanisms of action of CB2 agonists in reducing neuropathic pain
There are various possible explanations for why CB2 agonists have been effective in treating neuropathic pain in animal models. Understanding which of these are correct has major implications for the next steps in drug design and discovery based on the preclinical efficacy of current CB2 agonists (see Table 1 for references for the following section).
Clinical development
CB2 agonists are relatively recent developments in the study of potential treatments for neuropathic pain, and pre-clinical experimentation has been largely focused on improving efficacy of drug treatment and determining the mechanism of action. However, CB2 agonists have already been used in clinical trial. Cannabinor (formerly PRS-211,375) is a synthetic and water-soluble CB2-selective agonist that has been used in Phase II clinical trials by Pharmos Corporation, USA, as an analgesic.27
Conclusions
CB2 agonists are a promising new class of drugs for the treatment of neuropathic pain, circumventing the undesirable side effects associated with central CB1 receptor activation. CB2 agonists have shown efficacy in alleviating hyperalgesia and allodynia in various animal models of neuropathic pain. However, it is still unknown how and where these agonists are exerting their effects. There is evidence to suggest a role for both peripheral and central CB2 activation, most convincingly in
Conflict of interest
There is no conflict of interest.
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Scaffold hopping strategy toward original pyrazolines as selective CB <inf>2</inf> receptor ligands
2012, European Journal of Medicinal ChemistryCitation Excerpt :Recently, a number of researches tend to demonstrate the over-expression of CB2 receptors within the CNS under pathological inflammatory conditions, especially involve into the immune regulation role of microglial cells in brain [14–17]. These findings stimulated research endeavors with regards to the great potential of Target CB2 receptors to address the inflammation or neuropathic pain regulation issues leading eventually to drugs with a new mode of action [18,19]. For instance, the usefulness of CB2 receptor modulation was emphasized for neurodegenerative and neuroinflammatory disorders, such as Alzheimer's disease or Parkinson's disease [5,20], together with multiple sclerosis [21,22], and others [23].
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