Pharmacology/Drug Development

The current work examined the pharmacological potential of a selected flavanone derivative 2-hydroxyflavanone as a promising remedy for the treatment and management of pain. The selected flavanone derivative (2-HF) was evaluated for its analgesic and anti-inflammatory potentials following standard pharmacological protocols including hot plate, acetic acid-induced writhing and tail immersion tests. Naloxone and pentylenetetrazol were used to evaluate the potential implication of GABAergic and opioidergic mechanisms. The anti-inflammatory potential of 2-HF was confirmed using carrageenan-, serotonin- and histamine-induced paw edema models as well as a xylene-induced ear edema model. Furthermore, the anti-neuropathic potential of 2-HF was tested using a cisplatin-induced neuropathic pain model. Our sample, at the tested concentrations of 15, 30 and 45 mg kg, showed considerable analgesic, anti-inflammatory effects, as well as efficacy against neuropathic pain. Naloxone and pentylenetetrazol at 1 and 15 mg kg antagonized the anti-nociceptive activities of 2-hydroxyflavanone indicating the involvement of opioidergic and GABAergic mechanisms. In the static allodynia model, combination of gabapentin 75 mg kg with 2-HF at 15, 30, 45 mg kg doses exhibited considerable efficacy. In cold allodynia, 2-hydroxyflavanone, at doses of 15, 30 and 45 mg kg and in combination with gabapentin (75 mg kg), demonstrated prominent anti-allodynic effects. The paw withdrawal latency was considerably increased in gabapentin + cisplatin treated groups. Moreover, cisplatin + 2-hydroxyflavanone 15, 30, 45 mg kg showed increases in paw withdrawal latency. Likewise, considerable efficacy was observed for 2-hydroxyflavanone in thermal hyperalgesia and dynamic allodynia models. Our findings suggest that 2-hydroxyflavanone is a potential remedy for pain syndrome, possibly mediated through opioidergic and GABAergic mechanisms.

Endometriosis is a chronic, estrogen-dependent, inflammatory disease associated with pelvic pain, infertility, impaired sexual function, and psychological suffering. Therefore, tailored patient management appears of primary importance to address specific issues and identify the appropriate treatment for each woman. Over the years, abundant research has been carried out with the objective to find new therapeutic approaches for this multifaceted disease.

An estimated 54 million Americans currently suffer from debilitating arthritis. Patients who have exhausted conservative measures can be subject to chronic pain and resort to symptomatic management with anti-inflammatories, acetaminophen, and opioids. Cannabidiol (CBD) is a non-psychoactive cannabinoid that has shown promise in preclinical studies to reduce inflammation and pain associated with arthritis. The purpose of this study was to explore patient perceived effects of cannabidiol on symptoms of arthritis.

The loss of GABAergic inhibition is a mechanism that underlies neuropathic pain. Therefore, rescuing the GABAergic inhibitory tone through activation of GABAA receptors is a strategy to reduce neuropathic pain. This study was designed to elucidate the function of the spinal α6-containing GABAA receptor in physiological conditions and neuropathic pain in female and male rats. Results show that α6-containing GABAA receptor blockade or transient α6-containing GABAA receptor knockdown induces evoked hypersensitivity and spontaneous pain in naïve female rats. The α6 subunit is expressed in IB4+ and CGRP+ primary afferent neurons in the rat spinal dorsal horn and dorsal root ganglia (DRG), but not astrocytes. Nerve injury reduces α6 subunit protein expression in the central terminals of the primary afferent neurons and DRG, whereas intrathecal administration of positive allosteric modulators (PAMs) of the α6-containing GABAA receptor reduces tactile allodynia and spontaneous nociceptive behaviors in female, but not male, neuropathic rats and mice. Overexpression of the spinal α6 subunit reduces tactile allodynia and restores α6 subunit expression in neuropathic rats. PAMs of the α6-containing GABAA receptor induces a greater antiallodynic effect in females compared to male rats and mice. Finally, α6 subunit is expressed in humans. This receptor is found in CGRP+ and P2X3+ primary afferent fibers but not astrocytes in the human spinal dorsal horn. Our results suggest that the spinal α6-containing GABAA receptor has a sex-specific antinociceptive role in neuropathic pain, suggesting that this receptor may represent an interesting target to develop a novel treatment for neuropathic pain.

The exact mechanism and site of action of triptans in aborting migraine attacks remain under debate. We hypothesized that the clinical efficacy of triptans lies in aborting central sensitization and focused on the question of why triptans are headache-specific, i.e. highly effective in migraine and cluster headache and ineffective in extracephalic pain.

Neuropathic pain (NP) arises as a direct consequence of traumatic spinal cord injury (SCI), which leads to devastating consequences for people suffering from this condition since no specific treatment has been defined. One relevant mechanism in generating painful stimuli involves the direct participation of reactive oxygen species (ROS) at the cellular and subcellular levels. Cannabidiol (CBD) is one of the two most crucial cannabinoid components of the cannabis plant and has been proposed as a potential treatment for NP. Its antioxidant, neuroprotective and anti-inflammatory properties have been documented. However, there is insufficient evidence regarding CBD as treatment of NP induced by SCI or the mechanisms that underlie this effect. In this study, we evaluated the antinociceptive effect of CBD as an acute treatment after the nociceptive behaviors characteristic of NP were established (hypersensitivity threshold and hypersensitivity response). Furthermore, the participation of oxidative stress was determined by lipid peroxidation (LP) and glutathione concentration (GSH) in female Wistar rats with SCI. Acute treatment with CBD (2.5-20 mg/kg, i.p.) decreased nociceptive behaviors in a dose-dependent manner, decreased LP, and increased GSH concentration in injured tissue 15 days after injury. The findings of this study suggest that the antinociceptive effect induced by CBD is regulated by reducing oxidative stress by decreasing the LP and increasing the concentration of antioxidant (GSH) defenses.

Melatonin, through its G protein-coupled MT receptor, is implicated in analgesia, but the relationship between MT receptors and the opioid system remains elusive. In a model of rodent neuropathic pain (spared nerve injured, SNI), the selective melatonin MT agonist UCM924 reversed the allodynia (a pain response to a non-noxious stimulus), and this effect was nullified by the pharmacological blockade or genetic inactivation of the mu opioid receptor (MOR), but not the delta opioid receptor (DOR). Indeed, SNI MOR, but not DOR knockout mice, did not respond to the antiallodynic effects of the UCM924. Similarly, the non-selective opioid antagonist naloxone and the selective MOR antagonist CTOP blocked the effects of UCM924 in SNI rats, but not the DOR antagonist naltrindole (NTI). Electrophysiological recordings in the rostral-ventromedial medulla (RVM) revealed that the typical reduction of the firing activity of pro-nociceptive ON-cells, and the enhancement of the firing of the anti-nociceptive OFF-cells, induced by the microinjection of the MT agonist UCM924 into the ventrolateral periaqueductal gray (vlPAG) were blocked by MOR, but not DOR, antagonism. Immunohistochemistry studies showed that MT receptors are expressed in both excitatory (CaMKIIα ) and inhibitory (GAD65 ) neuronal cell bodies in the vlPAG (~2.16% total), but not RVM. Only 0.20% of vlPAG neurons co-expressed MOR and MT receptors. Finally, UCM924 treatment induced an increase in the enkephalin precursor gene (PENK) in the PAG of SNI mice. Collectively, the melatonin MT receptor agonism requires MORs to exert its antiallodynic effects, mostly through an inter-neuronal circuit involving MOR and MT receptors. This article is protected by copyright. All rights reserved.