Inhibitory effects of CB<sub>1</sub> and CB<sub>2</sub> receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats

Sagar, Devi Rani; Kelly, Sara; Millns, Paul; O'Shaughnessey, Celestine T.; Kendall, David A.; Chapman, Victoria

doi:10.1111/j.1460-9568.2005.04206.x

Cited by 138 publications

(151 citation statements)

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“…This inhibitory effect was reversed by pharmacologic blockade of CB 2 Rs (AM630) or was absent in CB 2 −/− mice, suggesting a CB 2 R-mediated effect. This finding is consistent with previous reports in which JWH133 or other CB 2 R agonists inhibited spontaneous and evoked neuronal firing to noxious stimuli in spinal cord and thalamus (44)(45)(46)(47) and inhibited excitatory neuronal firing in the prefrontal cortex (48). Thus, our electrophysiological data provide direct evidence demonstrating that the expressed CB 2 Rs in VTA DA neurons are functional, and that activation of these receptors inhibits VTA DA neuronal firing and decreases VTA DA neuronal excitability.…”

Section: Discussionsupporting

confidence: 82%

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Zhang

Gao

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

304

353

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Cannabinoid CB 2 receptors (CB 2 Rs) have been recently reported to modulate brain dopamine (DA)-related behaviors; however, the cellular mechanisms underlying these actions are unclear. Here we report that CB 2 Rs are expressed in ventral tegmental area (VTA) DA neurons and functionally modulate DA neuronal excitability and DA-related behavior. In situ hybridization and immunohistochemical assays detected CB 2 mRNA and CB 2 R immunostaining in VTA DA neurons. Electrophysiological studies demonstrated that activation of CB 2 Rs by JWH133 or other CB 2 R agonists inhibited VTA DA neuronal firing in vivo and ex vivo, whereas microinjections of JWH133 into the VTA inhibited cocaine self-administration. Importantly, all of the above findings observed in WT or CB 1 −/− mice are blocked by CB 2 R antagonist and absent in CB 2 −/− mice. These data suggest that CB 2 R-mediated reduction of VTA DA neuronal activity may underlie JWH133's modulation of DA-regulated behaviors.T he presence of functional cannabinoid CB 2 receptors (CB 2 Rs) in the brain has been controversial. When CB 2 Rs were first cloned, in situ hybridization (ISH) failed to detect CB 2 mRNA in brain (1). Similarly, Northern blot and polymerase chain reaction (PCR) assays failed to detect CB 2 mRNA in brain (2-5). Therefore, CB 2 Rs were considered "peripheral cannabinoid receptors" (1, 6).In contrast, other studies using ISH and radioligand binding assays detected CB 2 mRNA and receptor binding in rat retina (7), mouse cerebral cortex (8), and hippocampus and striatum of nonhuman primates (9). More recent studies using RT-PCR also detected CB 2 mRNA in the cortex, striatum, hippocampus, amygdala, and brainstem (9-14). Immunoblot and immunohistochemistry (IHC) assays detected CB 2 R immunoreactivity or immunostaining in various brain regions (13,(15)(16)(17)(18)(19)(20). The specificities of the detected CB 2 R protein and CB 2 -mRNA remain questionable, however, owing to a lack of controls using CB 1 −/− and CB 2 −/− mice in most previous studies (21). A currently accepted view is that brain CB 2 Rs are expressed predominantly in activated microglia during neuroinflammation, whereas brain neurons, except for a very small number in the brainstem, lack CB 2 R expression (21).On the other hand, we recently reported that brain CB 2 Rs modulate cocaine self-administration and cocaine-induced increases in locomotion and extracellular dopamine (DA) in the nucleus accumbens in mice (22). This finding is supported by recent studies demonstrating that systemic administration of the CB 2 R agonist O-1966 inhibited cocaine-induced conditioned place preference in WT mice, but not in CB 2 −/− mice (23), and that increased CB 2 R expression in mouse brain attenuates cocaine self-administration and cocaine-enhanced locomotion (19). In addition, brain CB 2 Rs may be involved in several DA-related CNS disorders, such as Parkinson's disease (24), schizophrenia (25), anxiety (26), and depression (27). The cellular mechanisms underlying CB 2 R modulation of DA-related behav...

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Section: Discussionsupporting

confidence: 82%

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Zhang

Gao

Liu

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

304

353

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“…Inhibitory effects of peripheral and spinal URB597 in SNL and sham-operated rats were blocked by AM251, demonstrating the contribution of CB 1 receptors. CB 1 receptor-mediated antinociception has been widely described in neuropathic rats (Herzberg et al, 1997;Mao et al, 2000;Bridges et al, 2001;Fox et al, 2001;Monhemius et al, 2001;Helyes et al, 2003;Lim et al, 2003;Scott et al, 2004;Pascual et al, 2005;Sagar et al, 2005). Our data are consistent with reports that CB 1 receptors mediate the inhibitory effects of FAAH inhibitors (Cravatt et al, 2001;Kathuria et al, 2003;Lichtman et al, 2004a,b;Wilson et al, 2004;Hohmann et al, 2005;Jayamanne et al, 2006).…”

Section: Discussionsupporting

confidence: 82%

“…Activation of both the cannabinoid 1 receptor (CB 1 ) and CB 2 reduces nociceptive processing in animal models of neuropathic pain (Hohmann, 2002;Howlett et al, 2002;Elmes et al, 2004;Sagar et al, 2005). Furthermore, nociceptive processing is tonically modulated by the endocannabinoids.…”

Section: Introductionmentioning

confidence: 99%

Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

Jhaveri¹,

Richardson²,

Kendall³

et al. 2006

J. Neurosci.

151

131

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“…This upregulation of CB2 receptors has been shown to have functional consequences, as activation of spinal CB2 receptors attenuates neuronal [37] and behavioural [32,42] nociceptive responses in models of neuropathic pain. In contrast to both mixed CB1 and CB2 agonists and selective CB1 agonists, activation of spinal CB2 receptors attenuated pain responses in neuropathic rats without altering nociceptive processing per se in control rats [37]. Studies using CB2 knockout mice report that effects of spinally administered CB2 agonists are absent in these animals [42], further consolidating the evidence for novel functional effects of spinal CB2 receptors in models of neuropathic pain.…”

Section: A Novel Role Of Cb2 Receptors In Chronic Pain Statesmentioning

confidence: 99%

Dynamic changes to the endocannabinoid system in models of chronic pain

Sagar

Burston

Woodhams

et al. 2012

Phil. Trans. R. Soc. B

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The analgesic effects of cannabinoid ligands, mediated by CB1 receptors are well established. However, the side-effect profile of CB1 receptor ligands has necessitated the search for alternative cannabinoid-based approaches to analgesia. Herein, we review the current literature describing the impact of chronic pain states on the key components of the endocannabinoid receptor system, in terms of regionally restricted changes in receptor expression and levels of key metabolic enzymes that influence the local levels of the endocannabinoids. The evidence that spinal CB2 receptors have a novel role in the modulation of nociceptive processing in models of neuropathic pain, as well as in models of cancer pain and arthritis is discussed. Recent advances in our understanding of the spinal location of the key enzymes that regulate the levels of the endocannabinoid 2-AG are discussed alongside the outcomes of recent studies of the effects of inhibiting the catabolism of 2-AG in models of pain. The complexities of the enzymes capable of metabolizing both anandamide (AEA) and 2-AG have become increasingly apparent. More recently, it has come to light that some of the metabolites of AEA and 2-AG generated by cyclooxygenase-2, lipoxygenases and cytochrome P450 are biologically active and can either exacerbate or inhibit nociceptive signalling.

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Inhibitory effects of CB₁ and CB₂ receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats

Cited by 138 publications

References 53 publications

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

Dynamic changes to the endocannabinoid system in models of chronic pain

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Inhibitory effects of CB1 and CB2 receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats

Cited by 138 publications

References 53 publications

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB 2 receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Analgesic Effects of Fatty Acid Amide Hydrolase Inhibition in a Rat Model of Neuropathic Pain

Dynamic changes to the endocannabinoid system in models of chronic pain

Contact Info

Product

Resources

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Inhibitory effects of CB₁ and CB₂ receptor agonists on responses of DRG neurons and dorsal horn neurons in neuropathic rats

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice

Cannabinoid CB ₂ receptors modulate midbrain dopamine neuronal activity and dopamine-related behavior in mice