1-(2′,4′-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice

Luongo, Livio; Palazzo, Enza; Tambaro, Simone; Giordano, C; Gatta, Luisa Benerini; Scafuro, Marika; Rossi, Francesca; Lazzari, Paolo; Pani, Luca; Novellis, Vito de; Malcangio, Marzia; Maione, Sabatino

doi:10.1016/j.nbd.2009.09.021

Cited by 103 publications

(84 citation statements)

References 72 publications

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“…Consistentwith these findings, repeated treatment with another selective CB2 ligand was also shown to be antinociceptive. NESS400 administration significantly attenuated mechanical allodynia and thermal hyperalgesia, and also decreased markers of microglia and astrocyte activation in the spinal cord of neuropathic mice at 7 days post-injury [43]. Similarly, repeated treatment with WIN55,212-2 produced a significant attenuation of pain behaviour and levels of markers of astrocytes activation in tumour-bearing mice [70] but had no effect on pain behaviour in neuropathic mice.…”

Section: Cb2 Receptor Modulation Of Spinal Immune Cell Functionmentioning

confidence: 88%

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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Section: Cb2 Receptor Modulation Of Spinal Immune Cell Functionmentioning

confidence: 88%

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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“…Indeed, an increased expression of CB2 receptors has been shown in microglial cells, as well as in astrocytes, in neuropathic pain conditions [25,26]. It has been underlined that CB2 receptors play a crucial role in the regulation of central immune responses during neuropathic pain [27,28]. Besides the well characterized CB1 and CB2 receptors, several reports have shown the existence of other receptors that represent potential targets to be included in the endocannabinoid system (eCBSS).…”

Section: The Endocannabinoid System and Patho-logical Painmentioning

confidence: 99%

Role of Endocannabinoids in Neuron-Glial Crosstalk

Luongo¹,

Palazzo²,

Novellis³

et al. 2010

TOPAINJ

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Evidence shows bidirectional crosstalk between neurons and glia, suggesting that glia play an active role in synaptic plasticity leading to chronic pain. Importantly, gliosis has been implicated in the development and maintenance of hyperalgesia or allodynia following chronic inflammation or nerve injury. Anandamide (AEA) and 2-arachidonoylglycerol (2-AG), or the lipoamino acid N-arachydonoyldopamine (NADA), are fatty acid derivative neurotransmitters, named endocannabinoids (eCBs). These perform several biological actions, via the activation of cannabinoid type 1 and 2 (CB1/CB2) receptors belonging to the G-protein-coupled receptor family. The eCBs are produced on demand by neurons or glial cells and it has been suggested that they might be involved in the crosstalk between astrocytes, microglia, oligodendrocytes and neurons. In chronic pain, the modified glial or neural activity also seems to be associated with changes in eCB levels in pain processing areas either in the spinal cord or the brain. The activation of the eCB system in microglia or astrocytes could be crucial in modulating axonal growth and synaptogenesis at the base of neural phenotypic changes. Furthermore, changes in eCBs levels have been suggested to affect the destiny of cells: death or survival may depend on a specific pain condition. Thus, although eCBs are emerging as neurotransmitters responsible for the regulation of glia-neuron crosstalk in chronic pain, the precise mechanisms leading to eCB production, the origin and the timecourse of eCB release, the eCB release switch from one cell type to the other and their movement or catabolism across the glial or neural cell membrane nevertheless still remain unknown. These issues together with alternative eCB targets will be addressed in the current review.

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“…It was reported that microglial activation in the spinal cord after PNI is suppressed by administration of CB 2 R agonists and in mice overexpressing CB 2 Rs [26,34]. Furthermore, CB 2 R agonists decrease the level of the proinflammatory cytokine IL-1 in the spinal cord [27]. These findings suggest that glial cells, especially microglia, are the target cells involved in suppressing PNI-induced tactile allodynia by CB 2 R agonists.…”

Section: Discussionmentioning

confidence: 81%

“…Several lines of evidence indicate that glial cells are the predominant cell type expressing CB 2 Rs in the spinal cord [21,26,27]. The time course of increased CB 2 R expression is similar to that of microglial activation, and the upregulation of CB 2 Rs also occurs in other diseases associated with microglial activation [32,33].…”

Section: Discussionmentioning

confidence: 99%

“…Because CB 2 R in the spinal cord is expressed in activated microglia after PNI [21,26,27], we investigated the function of CB 2 Rs on microglial activation in vitro using BV-2 cells, a well-known murine microglial cell line [28]. First, we performed a cAMP assay to confirm the expression of functional CB 2 Rs in BV-2 cells and found that JWH133 (100 nM) significantly decreased cAMP concentrations (Fig.…”

Section: Effect Of Jwh133 On Gene Expression Induced By Irf8 In Cultumentioning

confidence: 99%

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Spinal Cord is the Primary Site of Action of the Cannabinoid CB2 Receptor Agonist JWH133 that Suppresses Neuropathic Pain: Possible Involvement of Microglia

Shimoyama

Tsuda²,

Masuda

et al. 2014

TOPAINJ

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Neuropathic pain, a highly debilitating condition that commonly occurs after damage to the nervous system, is often resistant to commonly used analgesic agents such as non-steroidal anti-inflammatory drugs and even opioids. Several studies using rodent models reported that cannabinoid CB 2 receptor (CB 2 R) agonists are effective for treating chronic pain. However, the analgesic mechanism of CB 2 R agonists in neuropathic pain states is not fully understood. In this study, we investigated the role of CB 2 Rs in the development and maintenance phases of neuropathic pain, and the mechanism of the CB 2 R-mediated analgesic effect on neuropathic pain. In a rat model of neuropathic pain, systemic administration of JWH133, a CB 2 R agonist, markedly improved tactile allodynia, and this effect was prevented by intrathecal pretreatment with AM630, a CB 2 R antagonist. The antiallodynic effect of intrathecally administered JWH133 was inhibited by intrathecal pretreatment with pertussis toxin or forskolin. In the spinal cord, CB 2 R expression was significantly increased on post-operative day 3, and persisted for 2 weeks. Furthermore, repeated intrathecal administration of JWH133 notably attenuated the development of tactile allodynia after peripheral nerve injury. In a culture of microglia activated by overexpressing interferon regulatory factor 8, a transcription factor crucial for neuropathic pain, JWH133 treatment suppressed the increased expression of interleukin-1 . Our findings suggest that activation of CB 2 Rs upregulated in the spinal cord after nerve injury alleviates existing tactile allodynia through the G i/oadenylate cyclase signaling pathway and suppresses the development of allodynia. This process may reduce the inflammatory response of microglia. Therefore, spinal CB 2 Rs may be a therapeutic target for the treatment of neuropathic pain.

show abstract

1-(2′,4′-dichlorophenyl)-6-methyl-N-cyclohexylamine-1,4-dihydroindeno[1,2-c]pyrazole-3-carboxamide, a novel CB2 agonist, alleviates neuropathic pain through functional microglial changes in mice

Cited by 103 publications

References 72 publications

Dynamic changes to the endocannabinoid system in models of chronic pain

Dynamic changes to the endocannabinoid system in models of chronic pain

Role of Endocannabinoids in Neuron-Glial Crosstalk

Spinal Cord is the Primary Site of Action of the Cannabinoid CB2 Receptor Agonist JWH133 that Suppresses Neuropathic Pain: Possible Involvement of Microglia

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