Pharmacology of Cannabinoid Receptor Agonists and a Cyclooxygenase-2 Inhibitor in Rat Bone Tumor Pain

Cui, Jinghua; Ju, Jae Kyun; Yoon, Myung Ha

doi:10.1159/000354296

Cited by 10 publications

(3 citation statements)

References 34 publications

(50 reference statements)

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“…Besides, it has been observed that nabilone exerted higher efficacy in reducing hyperalgesia in women than in men whereas smoked cannabis containing THC elicited greater analgesia in men (Cooper and Craft, 2018). Studies conducted with only female rats have reported that the intrathecal administration of ACEA has prevented hyperalgesia associated with acute acrolein-induced cystitis (Jones et al, 2015) and reduced mechanical allodynia induced by a bone tumor in the tibia (Cui et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Spinal cannabinoid CB1 or CB2 receptors activation attenuates mechanical allodynia in streptozotocin-induced diabetic rats

Gonçalves¹,

Conceição²,

Jesus³

et al. 2020

Behavioural Pharmacology

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Diabetes is a chronic disease associated with a high number of complications such as peripheral neuropathy, which causes sensorial disturbances and may lead to the development of diabetic neuropathic pain (DNP). The current treatment for DNP is just palliative and the drugs may cause severe adverse effects, leading to discontinuation of treatment. Thus, new therapeutic targets need to be urgently investigated. Studies have shown that cannabinoids have promising effects in the treatment of several pathological conditions, including chronic pain. Thus, we aimed to investigate the acute effect of the intrathecal injection of CB1 or CB2 cannabinoid receptor agonists N-(2-chloroethyl)-5Z, 8Z, 11Z, 14Z-eicosatetraenamide (ACEA) or JWH 133, respectively (10, 30 or 100 μg/rat) on the mechanical allodynia associated with experimental diabetes induced by streptozotocin (60 mg/kg; intraperitoneal) in rats. Cannabinoid receptor antagonists CB1 AM251 or CB2 AM630 (1 mg/kg) were given before treatment with respective agonists to confirm the involvement of cannabinoid CB1 or CB2 receptors. Rats with diabetes exhibited a significant reduction on the paw mechanical threshold 2 weeks after diabetes induction, having the maximum effect observed 4 weeks after the streptozotocin injection. This mechanical allodynia was significantly improved by intrathecal treatment with ACEA or JWH 133 (only at the higher dose of 100 μg). Pre-treatment with AM251 or AM630 significantly reverted the anti-allodynic effect of the ACEA or JWH 133, respectively. Considering the clinical challenge that the treatment of DPN represents, this study showed for the first time, that the intrathecal cannabinoid receptors agonists may represent an alternative for the treatment of DNP.

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Section: Discussionmentioning

confidence: 99%

Spinal cannabinoid CB1 or CB2 receptors activation attenuates mechanical allodynia in streptozotocin-induced diabetic rats

Gonçalves¹,

Conceição²,

Jesus³

et al. 2020

Behavioural Pharmacology

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“…Spinally, CB1 receptors are expressed in neurons while CB2 receptors are expressed on microglia, where the CB1 agonists reduce excitatory transmitter release and CB2 receptors attenuate microglial activation [359,360]. Intrathecal delivery of both CB1 and CB2 preferring ligands reduced facilitated states such as the formalin model, hyperpathia in neuropathy models and in tumor bone pain in rodents [361][362][363]. As many of these ligands have very high cLogPs, appropriate formulation in spinally compatible vehicles is an important consideration in their development for spinal use.…”

Section: Cannabinoidsmentioning

confidence: 99%

Current and Future Issues in the development of spinal agents for the management of pain

Yaksh¹,

Fisher²,

Hockman³

et al. 2016

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Targeting analgesic drugs for spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn and this output informs the brain as to the peripheral environment. This encoding process is subject to strong upregulation resulting in hyperesthetic states and downregulation reducing the ongoing processing of nociceptive stimuli reversing the hyperesthesia and pain processing. The present review addresses the biology of spinal nociceptive processing as relevant to the effects of intrathecally-delivered drugs in altering pain processing following acute stimulation, tissue inflammation/injury and nerve injury. The review covers i) the major classes of spinal agents currently employed as intrathecal analgesics (opioid agonists, alpha 2 agonists; sodium channel blockers; calcium channel blockers; NMDA blockers; GABA A/B agonists; COX inhibitors; ii) ongoing developments in the pharmacology of spinal therapeutics focusing on less studied agents/targets (cholinesterase inhibition; Adenosine agonists; iii) novel intrathecal targeting methodologies including gene-based approaches (viral vectors, plasmids, interfering RNAs); antisense, and toxins (botulinum toxins; resniferatoxin, substance P Saporin); and iv) issues relevant to intrathecal drug delivery (neuraxial drug distribution), infusate delivery profile, drug dosing, formulation and principals involved in the preclinical evaluation of intrathecal drug safety.Keywords: Adenovirus transfection, dorsal horn, neurotoxins, pain pathways, spinal drug delivery, spinal analgesics, toxicity. RATIONALETargeting analgesic drugs for direct spinal delivery reflects the fact that while the conscious experience of pain is mediated supraspinally, input initiated by high intensity stimuli, tissue injury and/or nerve injury is encoded at the level of the spinal dorsal horn. Thus, high intensity (e.g., nociceptive) stimulation activates populations of small primary afferents, generating an intensity-dependent increase in activity of second order dorsal horn projection neurons. This excitation is transmitted through spinofugal projection pathways to higher centers, such as the somatosensory thalamus -somatosensory cortex, and to the medial thalamus -limbic cortices that are respectively believed to underlie the sensory-discriminative and affectivemotivational components of the pain experience [1-3]. The dorsal horn encoding process reflects a remarkable plasticity wherein the input-output function of the spinal dorsal horn is subject to pronounced regulation by local neuronal and nonneuronal circuits as well as supraspinal (bulbospinal) input. Thus, following tissue or nerve injury there is an enhanced neuronal response to moderate or low intensity stimuli, e.g., *Address correspondence to this author at the University of California, San Diego, Anesthesia Research Lab 0818, 9500 Gilman Dr. LaJolla, CA 92093, USA; ...

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“…Typically, they have been applied as thiazide and loop diuretics [45]. The sulfonamide COX-1/ COX-2 and COX-2 inhibitors such as Celecoxib, SC-558, Rofecoxib, and DuP-697 have been prescribed against inflammation [46,47], pain [48,49], and cancers [50,51]. Another area of sulfonamide drugs includes HIV protease [52] and reverse transcriptase inhibitors [53].…”

Section: Equation and Descriptorsmentioning

confidence: 99%

Indole-like Trk receptor antagonists

Tammiku-Taul

Park

Jaanson

et al. 2016

European Journal of Medicinal Chemistry

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The virtual screening for new scaffolds for TrkA receptor antagonists resulted in potential low molecular weight drug candidates for the treatment of neuropathic pain and cancer. In particular, the compound (Z)-3-((5-methoxy-1H-indol-3-yl)methylene)-2-oxindole and its derivatives were assessed for their inhibitory activity against Trk receptors. The IC50 values were computationally predicted in combination of molecular and fragment-based QSAR. Thereafter, based on the structure-activity relationships (SAR), a series of new compounds were designed and synthesized. Among the final selection of 13 compounds, (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-N-methyl-2-oxindole-5-sulfonamide showed the best TrkA inhibitory activity using both biochemical and cellular assays and (Z)-3-((5-methoxy-1-methyl-1H-indol-3-yl)methylene)-2-oxindole-5-sulfonamide was the most potent inhibitor of TrkB and TrkC.

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Pharmacology of Cannabinoid Receptor Agonists and a Cyclooxygenase-2 Inhibitor in Rat Bone Tumor Pain

Cited by 10 publications

References 34 publications

Spinal cannabinoid CB1 or CB2 receptors activation attenuates mechanical allodynia in streptozotocin-induced diabetic rats

Spinal cannabinoid CB1 or CB2 receptors activation attenuates mechanical allodynia in streptozotocin-induced diabetic rats

Current and Future Issues in the development of spinal agents for the management of pain

Indole-like Trk receptor antagonists

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