Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors

Agarwal, Nitin; Pacher, Pál; Tegeder, Irmgard; Amaya, Fumimasa; Constantin, Cristina; Brenner, Gary J.; Rubino, Tiziana; Michalski, Christoph; Marsicano, Giovanni; Monory, Krisztina; Mackie, Ken; Marian, Claudiu; Bátkai, Sándor; Parolaro, Daniela; Fischer, Michael J.M.; Reeh, Peter W.; Kunos, George; Kress, Michaela; Lutz, Beat; Woolf, Clifford J.; Kuner, Rohini

doi:10.1038/nn1916

Cited by 508 publications

(490 citation statements)

References 44 publications

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“…This was interpreted as indicating antinociceptive effects on a sensory level (Bloom and Dewey, 1978;Chesher et al, 1973), which would further agree with cannabinoid receptors being present in pain circuits from the peripheral sensory nerve endings up to the brain (Manzanares et al, 2006). Endocannabinoids are also involved in endogenous pain inhibition (Walker et al, 2001), as shown in models of chronic inflammatory and neuropathic pain (Agarwal et al, 2007;Bishay et al, 2010). Local injections of cannabinoid receptor agonists reduce pain in various rodent models (Agarwal et al, 2007;Kehl et al, 2003;Lozano-Ondoua et al, 2010).…”

Section: Intrinsic Connections (A Parameter)mentioning

confidence: 78%

“…Endocannabinoids are also involved in endogenous pain inhibition (Walker et al, 2001), as shown in models of chronic inflammatory and neuropathic pain (Agarwal et al, 2007;Bishay et al, 2010). Local injections of cannabinoid receptor agonists reduce pain in various rodent models (Agarwal et al, 2007;Kehl et al, 2003;Lozano-Ondoua et al, 2010). A few human studies also demonstrated a decreased sensitivity and increased tolerance to pain in a THC dose-dependent manner (Cooper et al, 2013;Greenwald and Stitzer, 2000), which is in line with the observation of reduced coupling between thalamus and S2 as the lateral spinothalamic tract is critical for the sensorydiscriminative processing of pain (Maihofner et al, 2006;Price, 2002).…”

Section: Intrinsic Connections (A Parameter)mentioning

confidence: 99%

“…CB 1 receptor activations have been associated with several perceptual and cognitive effects. They include an inhibition of chronic inflammatory and neuropathic pain (Agarwal et al, 2007;Bishay et al, 2010), a modulation of sensory information processing (Dervaux et al, 2013;Tart, 1970), often described as taking on new qualities, including nociception (Walker and Huang, 2002), a disruption of filtering of non-salient information (D'Souza et al, 2012) and attentional salience processing (Bhattacharyya et al, 2012;Solowij et al, 1991), and an extinction of aversive memories (Marsicano et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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Brain Mapping-Based Model of Δ9-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix

Walter

Oertel

Felden

et al. 2015

Neuropsychopharmacol

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Cannabinoids receive increasing interest as analgesic treatments. However, the clinical use of Δ 9 -tetrahydrocannabinol (Δ 9 -THC) has progressed with justified caution, which also owes to the incomplete mechanistic understanding of its analgesic effects, in particular its interference with the processing of sensory or affective components of pain. The present placebo-controlled crossover study therefore focused on the effects of 20 mg oral THC on the connectivity between brain areas of the pain matrix following experimental stimulation of trigeminal nocisensors in 15 non-addicted healthy volunteers. A general linear model (GLM) analysis identified reduced activations in the hippocampus and the anterior insula following THC administration. However, assessment of psychophysiological interaction (PPI) revealed that the effects of THC first consisted in a weakening of the interaction between the thalamus and the secondary somatosensory cortex (S2). From there, dynamic causal modeling (DCM) was employed to infer that THC attenuated the connections to the hippocampus and to the anterior insula, suggesting that the reduced activations in these regions are secondary to a reduction of the connectivity from somatosensory regions by THC. These findings may have consequences for the way THC effects are currently interpreted: as cannabinoids are increasingly considered in pain treatment, present results provide relevant information about how THC interferes with the affective component of pain. Specifically, the present experiment suggests that THC does not selectively affect limbic regions, but rather interferes with sensory processing which in turn reduces sensory-limbic connectivity, leading to deactivation of affective regions.

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Section: Intrinsic Connections (A Parameter)mentioning

confidence: 78%

Section: Intrinsic Connections (A Parameter)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Brain Mapping-Based Model of Δ9-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix

Walter

Oertel

Felden

et al. 2015

Neuropsychopharmacol

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“…The pain behavior of the SNS-Cre mouse line does not differ from that of wild-type littermates (38), suggesting that the observed hypersensitive phenotype is due to the deletion of NEDD4-2 and not to the expression of Cre recombinase in Na v 1.8-positive nociceptors. The possibility that these differences may also involve non-nociceptive neurons that are potentially subject to Cre recombination cannot be ruled out, as Na v 1.8 expression was recently shown to extend to larger DRG neurons (39).…”

Section: Discussionmentioning

confidence: 93%

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Laedermann

Cachemaille²,

Kirschmann³

et al. 2013

J. Clin. Invest.

114

160

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Peripheral neuropathic pain is a disabling condition resulting from nerve injury. It is characterized by the dysregulation of voltage-gated sodium channels (Na v s) expressed in dorsal root ganglion (DRG) sensory neurons. The mechanisms underlying the altered expression of Na v s remain unknown. This study investigated the role of the E3 ubiquitin ligase NEDD4-2, which is known to ubiquitylate Na v s, in the pathogenesis of neuropathic pain in mice. The spared nerve injury (SNI) model of traumatic nerve injury-induced neuropathic pain was used, and an Na v 1.7-specific inhibitor, ProTxII, allowed the isolation of Na v 1.7-mediated currents. SNI decreased NEDD4-2 expression in DRG cells and increased the amplitude of Na v 1.7 and Na v 1.8 currents. The redistribution of Na v 1.7 channels toward peripheral axons was also observed. Similar changes were observed in the nociceptive DRG neurons of Nedd4L knockout mice (SNS-Nedd4L -/-). SNS-Nedd4L -/-mice exhibited thermal hypersensitivity and an enhanced second pain phase after formalin injection. Restoration of NEDD4-2 expression in DRG neurons using recombinant adenoassociated virus (rAAV2/6) not only reduced Na v 1.7 and Na v 1.8 current amplitudes, but also alleviated SNI-induced mechanical allodynia. These findings demonstrate that NEDD4-2 is a potent posttranslational regulator of Na v s and that downregulation of NEDD4-2 leads to the hyperexcitability of DRG neurons and contributes to the genesis of pathological pain.

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“…[16] However, only peripheral CBr1 on nociceptors contribute to antinociception in inflammatory and neuropathic pain models. [1] CBr2 are found on immune cells [31,41] and keratinocytes [15,16]. CBr2 on keratinocytes mediates antinociception via opioid release.…”

Section: Discussionmentioning

confidence: 99%

Peripheral cannabinoids attenuate carcinoma-induced nociception in mice

Guerrero

Quang

Dekker³

et al. 2008

Neuroscience Letters

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We investigated the cannabinoid receptor (CBr) agonists Win55,212-2 (non-selective) and AM1241 (CBr2 selective) and the peripheral receptor (CBr1) in carcinoma-induced pain using a mouse model. Tumors were induced in the hind paw of female mice by local injection of a human oral squamous cell carcinoma (SCC). Significant pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, began at four days after SCC inoculation and lasted to 18 days. Local administration of Win55,212-2 (10 mg/kg) and AM1241 (10 mg/kg) significantly elevated withdrawal thresholds, indicating an antinociceptive effect. Ipsilateral expression of CBr1 protein in L5 DRG was significantly upregulated compared to ipsilateral L4 DRG and in normal tissue. These findings support the suggestion that cannabinoids are capable of producing antinociception in carcinoma-induced pain.

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Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors

Cited by 508 publications

References 44 publications

Brain Mapping-Based Model of Δ9-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix

Brain Mapping-Based Model of Δ9-Tetrahydrocannabinol Effects on Connectivity in the Pain Matrix

Dysregulation of voltage-gated sodium channels by ubiquitin ligase NEDD4-2 in neuropathic pain

Peripheral cannabinoids attenuate carcinoma-induced nociception in mice

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