Browse by Audience
Prescription opioid abuse is a global crisis. New treatment strategies for pain and opioid use disorders are urgently required. We evaluated the effects of RVK4-40, a highly selective dopamine (DA) D receptor (DR) antagonist, on the rewarding and analgesic effects of oxycodone, the most commonly abused prescription opioid, in rats and mice. Systemic administration of RVK4-40 dose-dependently inhibited oxycodone self-administration and shifted oxycodone dose-response curves downward in rats. Pretreatment with RVK4-40 also dose-dependently lowered break-points for oxycodone under a progressive-ratio schedule. To determine whether a DA-dependent mechanism underlies the impact of D antagonism in reducing opioid reward, we used optogenetic approaches to examine intracranial self-stimulation (ICSS) maintained by optical activation of ventral tegmental area (VTA) DA neurons in DAT-Cre mice. Photoactivation of VTA DA in non-drug treated mice produced robust ICSS behavior. Lower doses of oxycodone enhanced, while higher doses inhibited, optical ICSS. Pretreatment with RVK4-40 blocked oxycodone-enhanced brain-stimulation reward. By itself, RVK4-40 produced a modest dose-dependent reduction in optical ICSS. Pretreatment with RVK4-40 did not compromise the antinociceptive effects of oxycodone in rats, and RVK4-40 alone produced mild antinociceptive effects without altering open-field locomotion or rotarod locomotor performance. Together, these findings suggest RVK4-40 may permit a lower dose of prescription opioids for pain management, potentially mitigating tolerance and dependence, while diminishing reward potency. Hence, development of RVK4-40 as a therapy for the treatment of opioid use disorders and/or pain is currently underway.
Learn More >In 2018, three calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies, erenumab, fremanezumab and galcanezumab, were approved in various parts of the world, including Europe and the US, and another, eptinezumab, is pending, for the prevention of migraine. In this article, episodic migraine treatment is reviewed, although these medicines are approved and are just as effective for chronic migraine. These new medicines usher a new phase in the preventive management of migraine with migraine-specific treatments. Data from phase III trials of CGRP pathway monoclonal antibodies have shown they are efficacious, with adverse effect rates comparable to placebo. The combination of clear efficacy and excellent tolerability will be welcome in an area where poor adherence to current preventives is common. Rimegepant, ubrogepant and lasmiditan are migraine-specific acute therapies yet to be approved by regulators. Phase III data for the respective CGRP receptor antagonists, the gepants, and the serotonin 5-HT receptor agonist, the ditan, have been positive and free of cardiovascular adverse effects. These medicines are not vasoconstrictors. When approved, they could meet the acute therapy demand of patients with cardiovascular risk factors where triptans are contraindicated. Beyond this, gepants will see the most disruptive development in migraine management in generations with medicines that can have both acute and preventive effects, the latter evidenced by data from the discontinued drug telcagepant and the early-phase drug atogepant. Moreover, one can expect no risk of medication overuse syndromes with gepants since the more patients take, the less migraines they have. During the next years, as experience with monoclonal antibodies grows in clinical practice, we can expect an evolution in migraine management to take shape. Clinicians will be able to offer treatment patients want rather than trying to fit migraineurs into therapeutic boxes for their management. Despite pessimistic susurrations of a largely addlepated form, many patients, and physicians, will welcome new options, and the challenges of new treatment paradigms, with optimism.
Learn More >Cannabinoid receptors type 1 (CB) and type 2 (CB) are promising targets for a number of diseases, including obesity, neuropathic pain, and multiple sclerosis, among others. Upon ligand-mediated activation of these receptors, multiple receptor conformations could be stabilized, resulting in a complex pattern of possible intracellular effects. Although numerous compounds have been developed and widely used to target cannabinoid receptors, their mode of action and signaling properties are often only poorly characterized. From a drug development point of view, unraveling the underlying complex signaling mechanism could offer the possibility to generate medicines with the desired therapeutic profile. Recently, an increased interest has emerged for the development of agonists that are signaling pathway-selective and thereby do not evoke on-target adverse effects. This phenomenon, in which specific pathways are preferred upon receptor activation by certain ligands, is also known as 'biased signaling'. For a particular group of cannabinoid receptor ligands (i.e. CB/CB agonists), namely the synthetic cannabinoid receptor agonists (SCRAs), the research on biased signaling is still in its infancy and interesting outcomes are only recently being revealed. Therefore, this review aims at providing insights into the recent knowledge about biased agonism mediated by SCRAs so far. In addition, as these outcomes are obtained using a distinct panel of functional assays, the accompanying difficulties and challenges when comparing functional outcomes are critically discussed. Finally, some guidance on the conceptualization of ideal in vitro assays for the detection of SCRA-mediated biased agonism, which is also relevant for compounds belonging to other chemical classes, is provided.
Learn More >A phase 2, double-blind, placebo-controlled study to evaluate the efficacy and safety of erenumab for the prevention of episodic migraine in Japanese patients was conducted.
Learn More >Cannabis is commonly used to manage chronic pain, but cannabis use patterns among individuals with chronic pain has not been well-characterized. We report cannabinoid, administration route, and product selection preferences among medical cannabis users with chronic pain from an ongoing, online survey. We also examined whether these preferences are affected by differences in sex, intentions behind use (medical only [MED] vs. medical + recreational [MEDREC]), and experience with cannabis (novice: <1 year vs. experienced: ≥1 year). 1,321 participants (59% female) completed the survey. 76.5% of participants used cannabis every day. 93.4% used 2 or more administration routes, with 72.5% using 3 or more. Female, MED, and novice users were less likely to smoke or vaporize (all p < 0.0001), but more likely to rank edibles, tinctures, and topicals as a first-choice administration route than their counterparts. Female and MED users also preferred low THC: high CBD ratios significantly more than their counterparts. Overall, only 2.6% of participants selected cannabis products with input from a medical professional, although 54.9% relied on advice from dispensary employees. More male, MEDREC, and experienced users selected products based on factors that reflected greater comfort with cannabis (e.g., smell, visual properties, cannabis variety). The wide variability in cannabis use among these different groups indicates the need for further research to investigate how specific use routines relate to clinical outcomes. Perspective: Medical cannabis users with chronic pain show distinct differences in cannabinoid preferences and administration associated with user sex, intentions behind use, and experience with cannabis. This article highlights the wide variability in cannabis preferences among medical cannabis users with chronic pain, which may be relevant for clinical outcomes.
Learn More >This trial evaluated the efficacy and safety of GZ389988A, a tropomyosin receptor kinase A (TrkA) inhibitor, in subjects with painful knee osteoarthritis (OA).
Learn More >Wnt signaling pathway has been investigated extensively for its diverse metabolic and pain modulating mechanisms and recently its involvement has been postulated in the development of neuropathic pain. However, there are no reports as yet on involvement of Wnt signaling pathway in one of the most debilitating neurovascular complication of diabetes, i.e, diabetic peripheral neuropathy (DPN). Thus, in the present study, involvement of Wnt signaling was investigated in DPN using Wnt signaling inhibitors namely LGK974 (Porcupine inhibitor), NSC668036 (Disheveled inhibitor) and PNU74654 (β-catenin inhibitor). Diabetes was induced by a single intraperitoneal injection of streptozotocin (STZ) (50 mg/kg) to male Sprague Dawley rats. Diabetic rats after six weeks of diabetes induction showed increased expression of Wnt signaling proteins in the spinal cord (L4-L6 lumbar segment), dorsal root ganglions (DRGs) and sciatic nerves. Subsequent increase in inflammation, endoplasmic reticulum (ER) stress and loss of intraepidermal nerve fiber density (IENFD) was also observed, leading to neurobehavioral and nerve functional deficits in diabetic rats. Intrathecal administration of Wnt signaling inhibitors (each at doses of 10 and 30 µM) in diabetic rats showed improvement in pain-associated behaviors (heat, cold & mechanical hyperalgesia) and nerve functions (motor, sensory nerve conduction velocities and nerve blood flow) by decreasing the expression of Wnt pathway proteins, inflammatory marker, matrix metalloproteinase 2 (MMP2), ER stress marker, glucose-regulated protein 78 (GRP78) and improving IENFD. All these results signify the neuroprotective potential of Wnt signaling inhibitors in DPN. Perspective: This study emphasizes the involvement of Wnt signaling pathway in diabetic peripheral neuropathy (DPN). Blockade of this pathway using Wnt inhibitors provided neuroprotection in experimental DPN in rats. This study may provide a basis for exploring the therapeutic potential of Wnt inhibitors in DPN patients.
Learn More >The search for new ligands to treat neuropathic pain remains a challenge. Recently, oxytocin has emerged as an interesting molecule modulating nociception at central and peripheral levels, but no attempt has been made to evaluate the effect of recurrent oxytocin administration in neuropathic pain. Using male Wistar rats with spinal nerve ligation, we evaluated the effects of recurrent spinal (1 nmol; given by lumbar puncture) or peripheral (31 nmol; given by intraplantar injection in the ipsilateral paw to spinal nerve ligation) oxytocin administration on pain-like behavior in several nociceptive tests (tactile allodynia and thermal and mechanical hyperalgesia) on different days. Furthermore, we used an electrophysiological approach to analyze the effect of spinal 1 nmol oxytocin on the activity of spinal dorsal horn wide dynamic range cells. In neuropathic rats, spinal or peripheral oxytocin partially restored the nociceptive threshold measured with the von Frey filaments (tactile allodynia), Hargreaves (thermal hyperalgesia) and Randall-Selitto (mechanical hyperalgesia) tests for 12 days. These results agree with electrophysiological data showing that spinal oxytocin diminishes the neuronal firing of the WDR neurons evoked by peripheral stimulation. This effect was associated with a decline in the activity of primary afferent Aδ- and C-fibers. The above findings show that repeated spinal or peripheral oxytocin administration attenuates the pain-like behavior in a well-established model of neuropathic pain. This study provides a basis for addressing the therapeutic relevance of oxytocin in chronic pain conditions.
Learn More >The amygdala plays a critical role in emotional-affective aspects of behaviors and pain modulation. The central nucleus of amygdala (CeA) serves major output functions, and neuroplasticity in the CeA is linked to pain-related behaviors in different models. Activation of G-coupled group II metabotropic glutamate receptors (mGluRs), which consist of mGluR2 and mGluR3, can decrease neurotransmitter release and regulate synaptic plasticity. Group II mGluRs have emerged as targets for neuropsychiatric disorders and can inhibit pain-related processing and behaviors. Surprisingly, site and mechanism of antinociceptive actions of systemically applied group II mGluR agonists are not clear. Our previous work showed that group II mGluR activation in the amygdala inhibits pain-related CeA activity, but behavioral and spinal consequences remain to be determined. Here we studied the contribution of group II mGluRs in the amygdala to the antinociceptive effects of a systemically applied group II mGluR agonist (LY379268) on behavior and spinal dorsal horn neuronal activity, using the kaolin/carrageenan-induced knee joint arthritis pain model. Audible and ultrasonic vocalizations (emotional responses) and mechanical reflex thresholds were measured in adult rats with and without arthritis (5-6 h postinduction). Extracellular single-unit recordings were made from spinal dorsal horn wide dynamic range neurons of anesthetized (isoflurane) rats with and without arthritis (5-6 h postinduction). Systemic (intraperitoneal) application of a group II mGluR agonist (LY379268) decreased behaviors and activity of spinal neurons in the arthritis pain model but not under normal conditions. Stereotaxic administration of LY379268 into the CeA mimicked the effects of systemic application. Conversely, stereotaxic administration of a group II mGluR antagonist (LY341495) into the CeA reversed the effects of systemic application of LY379268 on behaviors and dorsal horn neuronal activity in arthritic rats. The data show for the first time that the amygdala is the critical site of action for the antinociceptive behavioral and spinal neuronal effects of systemically applied group II mGluR agonists.
Learn More >Pain is a frequent clinical symptom with significant impact on the patient's well-being. Therefore, adequate pain management is of utmost importance. While cannabinoids have become a more popular alternative to traditional types of pain medication among patients, the quality of evidence supporting the use of cannabinoids has been questioned. The beneficial and harmful effects of cannabinoids in patients with pain is unknown. Accordingly, we aim to assess the efficacy, tolerability and safety of cannabinoids (herbal, plant-derived extracts and synthetic) compared with placebo or no intervention for any type of pain.
Learn More >