The Role of the Cannabinoid CB2 Receptor in Pain Transmission and Therapeutic Potential of Small Molecule CB2 Receptor Agonists

Whiteside, Garth T.; Lee, G. P.; Valenzano, Kenneth J.

doi:10.2174/092986707780363023

Cited by 119 publications

(80 citation statements)

References 114 publications

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“…Although this receptor is primarily found in cells of the immune system, credible data supports the expression of CB 2 in neurons under certain circumstances (Van Sickle et al, 2005, Wotherspoon et al, 2005. However, while its biology is fascinating (Whiteside et al, 2007) a consideration of this receptor is beyond the scope of the current review. There are additional receptors that can interact with exogenous and endogenous cannabinoids, including GPR55 (Pertwee, 2007).…”

Section: Introductionmentioning

confidence: 92%

Signaling via CNS cannabinoid receptors

Mackie

2008

Molecular and Cellular Endocrinology

104

102

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Because of the prominent psychoactive effects of cannabis and its preparations, much research has focused on the actions of cannabinoids, the primary psychoactive components of cannabis, on neuronal function. A convergence of research has identified (1) cannabinoid receptors, (2) endogenous compounds that activate these receptors (endocannabinoids), and (3) drugs that interact with these receptors and the proteins that synthesize and degrade the endocannabinoids. This review will first consider how endogenous cannabinoids signal through cannabinoid receptors and the various forms of synaptic plasticity mediated by endocannabinoids. Next the interactions between exogenous cannabinoids such as Δ 9 -tetrahydrocannabinol and endocannabinoids and endocannabinoid-mediated plasticity will be examined. Finally, a model will be presented that can explain the prominent psychoactivity of these plant-derived cannabinoids.

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Section: Introductionmentioning

confidence: 92%

Signaling via CNS cannabinoid receptors

Mackie

2008

Molecular and Cellular Endocrinology

104

102

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“…Cannabinoids are efficacious in suppressing hyperalgesia and allodynia in animal models of neuropathic pain through CB 1 and CB 2 mechanisms [13][14][15][16][17][18][19][20]. Different classes of cannabinoids (i.e., synthetic endocannabinoids, CB 1 agonists, mixed CB 1 /CB 2 agonists, CB 2 agonists and endocannabinoid modulators) all suppress neuropathic pain behavior in animals [21].…”

Section: Preclinical Studiesmentioning

confidence: 99%

Cannabinoids For the Treatment of Neuropathic Pain: Are They Safe and Effective?

Gutierrez

Hohmann²

2011

Future Neurol.

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The isolation of D 9 -tetrahydrocannabinol (THC), the major psychoactive ingredient in cannabis, set the stage for the discovery of an endogenous cannabinoid (endocannabinoid) transmitter system [1]. Endogenous signaling molecules for this system were subsequently isolated [2,3]. Anandamide [4] and 2-arachidonoylglycerol (2-AG) [2,3], the best characterized endocannabinoids isolated to date, bind to and activate cannabinoid CB 1 and CB 2 receptors. CB 1 is the primary cannabinoid receptor found in the CNS [5], whereas CB 2 is predominantly, but not exclusively, found in the immune system [6][7][8]. The discovery of cannabinoid receptors allowed researchers to synthesize cannabinoids and characterize their pain-relieving properties. Anandamide and 2-AG are degraded by the enzymes fatty-acid amide hydrolase and monoacylglycerol lipase [9], respectively. Enzymes catalyzing endocannabinoid breakdown also represent targets for analgesic drug development. This article will briefly summarize the findings of preclinical and clinical studies evaluating the therapeutic and side-effect profile of cannabinoids as pharmacotherapies for neuropathic pain. Neuropathic painNeuropathic pain is caused by a primary lesion or dysfunction in the nervous system [10]. Spontaneous (ongoing, paroxysm) and evoked types of pain (hyperalgesia and allodynia) are present [11]. Hyperalgesia refers to an increase in response to stimuli that normally produces pain. Allodynia refers to pain caused by stimuli that are normally not painful. Neuropathic pain may arise from illness, be drug-induced or caused by toxin exposure [11]. Different patients or types of neuropathic pain may respond differently to standard drug interventions. NSAIDs [12], antidepressants, anticonvulsants and opioids [11,12] are all used to treat neuropathic pain. However, no single treatment provides complete relief from neuropathic pain, and adverse side effects limit their therapeutic efficacy. For example, patients treated with opioids develop sedation, nausea, constipation, respiratory depression, tolerance and hyperalgesia [101]. Identification of alternative therapeutics that provide adequate pain relief in the absence of adverse side effects remains a strong clinical need. Preclinical studiesCannabinoids are efficacious in suppressing hyperalgesia and allodynia in animal models of neuropathic pain through CB 1 and CB 2 mechanisms [13][14][15][16][17][18][19][20]. Different classes of cannabinoids (i.e., synthetic endocannabinoids, CB 1 agonists, mixed CB 1 /CB 2 agonists, CB 2 agonists and endocannabinoid modulators) all suppress neuropathic pain behavior in animals [21]. Efficacy has been demonstrated in animal models of traumatic nerve injury (i.e., chronic constriction injury [22], partial nerve ligation [23] and spinal nerve ligation [24] models) and in neuropathy models produced by metabolic challenges or toxins (streptozotocin-and chemotherapy-induced neuropathy) [21]."Cannabinoids are efficacious in suppressing hyperalgesia and allodynia in animal models of neur...

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“…Cannabinoid (CB) receptor agonists have been shown to be effective in attenuation of pain-related behaviors in a wide variety of animal models (Hama and Sagen, 2007a; Hohmann, 2005; Pertwee, 2001; Rahn and Hohmann, 2009; Whiteside et al, 2007). The potent mixed CB agonist WIN 55,212-2 can reduce neuropathic pain symptoms in an HIV-SN model (Wallace et al, 2007a,b).…”

Section: Introductionmentioning

confidence: 99%

Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy

et al. 2015

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Distal sensory neuropathies are a hallmark of HIV infections and can result in persistent and disabling pain despite advances in antiretroviral therapies. HIV-sensory neuropathic (HIV-SN) pain may be amenable to cannabinoid treatment, but currently available agonist treatments are limited by untoward side effects and potential for abuse in this patient population. Fatty acid amide hydrolase (FAAH) inhibitors may offer an alternative approach by inhibiting the degradation of endocannabinoids with purportedly fewer untoward CNS side effects. In order to evaluate this potential approach in the management of HIV-SN pain, the recombinant HIV envelope protein gp120 was applied epineurally to the rat sciatic nerve to induce an HIV-SN-like pain syndrome. Two distinct FAAH inhibitory compounds, URB597 and PF-3845 were tested, and contrasted with standard antinociceptive gabapentin or vehicle treatment, for attenuation of tactile allodynia, cold allodynia, and mechanical hyperalgesia. Both FAAH inhibitors markedly reduced cold and tactile allodynia with limited anti-hyperalgesic effects. Peak antinociceptive effects produced by both agents were more modest than gabapentin in reducing tactile allodynia with similar potency ranges. URB597 produced comparable cold anti-allodynic effects to gabapentin, and the effects of both FAAH inhibitors were longer lasting than gabapentin. To assess the contribution of cannabinoid receptors in these antinociceptive effects, CB1 antagonist AM251 or CB2 antagonist SR144528 were tested in conjunction with FAAH inhibitors. Results suggested a contribution of both CB1- and CB2-mediated effects, particularly in reducing tactile allodynia. In summary, these findings support inhibition of endocannabinoid degradation as a promising target for management of disabling persistent HIV-SN pain syndromes.

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The Role of the Cannabinoid CB2 Receptor in Pain Transmission and Therapeutic Potential of Small Molecule CB2 Receptor Agonists

Cited by 119 publications

References 114 publications

Signaling via CNS cannabinoid receptors

Signaling via CNS cannabinoid receptors

Cannabinoids For the Treatment of Neuropathic Pain: Are They Safe and Effective?

Attenuation of persistent pain-related behavior by fatty acid amide hydrolase (FAAH) inhibitors in a rat model of HIV sensory neuropathy

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