A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain

Kehl, Lois J.; Hamamoto, Darryl T.; Wacnik, Paul W.; Croft, Devin L; Norsted, Blake D; Wilcox, George L.; Simone, Donald A.

doi:10.1016/s0304-3959(02)00450-5

Cited by 102 publications

(65 citation statements)

References 71 publications

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“…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: 52%

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: 52%

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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“…[44] Kehl et al found that the antinociceptive effects of systemic cannabinoids on osteolytic sarcoma induced nociception were mediated via CBr1. [21] CBr1 are expressed at central and peripheral nerve terminals and in keratinocytes after being synthesized in DRG. [16] However, only peripheral CBr1 on nociceptors contribute to antinociception in inflammatory and neuropathic pain models.…”

Section: Discussionmentioning

confidence: 99%

“…[21] We tested whether a local CBr2 agonist produces antinociception. Our findings suggest that a peripheral CBr2 agonist could provide relief for cancer patients.…”

Section: Discussionmentioning

confidence: 99%

“…[2,10,19] In a murine bone sarcoma pain model, systemic cannabinoids act through CBr1. [15,21] However, the role of peripheral CBr1 and CBr2 receptors in soft tissue carcinoma pain is not known. We hypothesize that cannabinoid agonists are analgesic with carcinoma induced pain and that the site of action is within the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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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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“…In preliminary studies, THC produced analgesia equivalent to that of codeine in patients with cancer pain (Noyes et al, 1975). Using a murine model of bone cancer pain, we found that a cannabinoid (WIN 55,212-2) attenuated (~50%) deep-tissue hyperalgesia produced by implantation of fibrosarcoma cells into the humerus (Kehl et al, 2003). The aim of this study was to determine if a more potent cannabinoid, CP 55,940, attenuates tumor-evoked cutaneous mechanical hyperalgesia in a well-characterized murine model of cancer pain.…”

Section: Introductionmentioning

confidence: 99%

Acute and chronic administration of the cannabinoid receptor agonist CP 55,940 attenuates tumor-evoked hyperalgesia

Hamamoto

Giridharagopalan

Simone

2007

European Journal of Pharmacology

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Patients with cancer frequently report pain that can be difficult to manage. This study examined the antihyperalgesic effects of a cannabinoid receptor agonist, CP 55,940, in a murine model of cancer pain. Implantation of fibrosarcoma cells into and around the calcaneous bone in mice produced mechanical hyperalgesia (decreased paw withdrawal thresholds and increased frequency of paw withdrawals). On day 13 after implantation, mechanical hyperalgesia, nociception, and catalepsy were assessed. Mice were randomly assigned to receive CP 55,940 (0.01-3 mg/kg, i.p.) or vehicle and behavioral measures were redetermined. CP 55,940 dose-dependently attenuated tumor-evoked mechanical hyperalgesia. To examine the effect of catalepsy on the antihyperalgesic effect of CP 55,940, mice with tumor-evoked hyperalgesia were pretreated with the dopamine agonist apomorphine prior to administration of CP 55,940. Apomorphine attenuated the cataleptic effect of CP 55,940 but did not attenuate its antihyperalgesic effect. In a separate group of mice with tumorevoked hyperalgesia, administration of the dopamine antagonist spiperone produced catalepsy that was ~2.5 fold greater than that produced by CP 55,490. Whereas this dose of CP 55,940 completely reversed tumor-evoked mechanical hyperalgesia, spiperone only attenuated mechanical hyperalgesia by ~35%. Thus, the cataleptic effects of CP 55,940 did not fully account for its antihyperalgesic effect. The antihyperalgesic effect of CP 55,940 was mediated via the cannabinoid CB 1 but not CB 2 receptor. Finally, repeated administration of CP 55,940 produced a short-term and a longer term attenuation of tumor-evoked hyperalgesia. These results suggest that cannabinoids may be a useful alternative or adjunct therapy for treating cancer pain.

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A cannabinoid agonist differentially attenuates deep tissue hyperalgesia in animal models of cancer and inflammatory muscle pain

Cited by 102 publications

References 71 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

Peripheral cannabinoids attenuate carcinoma-induced nociception in mice

Acute and chronic administration of the cannabinoid receptor agonist CP 55,940 attenuates tumor-evoked hyperalgesia

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