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To evaluate the long-term safety and tolerability of ubrogepant for the acute treatment of migraine.
Learn More >Chemotherapy induced peripheral neuropathy (CIPN), a toxic side effect of some cancer treatments, negatively impacts patient outcomes and drastically reduces survivor's quality of life (QOL). Uncovering the mechanisms driving chemotherapy-induced CIPN is urgently needed to facilitate the development of effective treatments, as currently there are none. Observing that C57BL/6 (B6) and 129SvEv (129) mice are respectively sensitive and resistant to Paclitaxel-induced pain, we investigated the involvement of the gut microbiota in this extreme phenotypic response. Reciprocal gut microbiota transfers between B6 and 129 mice as well as antibiotic depletion causally linked gut microbes to Paclitaxel-induced pain sensitivity and resistance. Microglia proliferated in the spinal cords of Paclitaxel treated mice harboring the pain-sensitive B6 microbiota but not the pain-resistant 129 microbiota, which exhibited a notable absence of infiltrating immune cells. Paclitaxel decreased the abundance of Akkermansia muciniphila, which could compromise barrier integrity resulting in systemic exposure to bacterial metabolites and products – that acting via the gut-immune-brain axis – could result in altered brain function. Other bacterial taxa that consistently associated with both bacteria and pain as well as microglia and pain were identified, lending support to our hypothesis that microglia are causally involved in CIPN, and that gut bacteria are drivers of this phenotype.
Learn More >Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α-adrenergic receptor (αAR), seeking new αAR agonists chemotypes that lack the sedation conferred by known αAR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G and G signaling. Experimental structures of αAR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC) of 52 nanomolar] and two analogs, '7075 and PS75 (EC 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.
Learn More >Bladder pain syndrome/interstitial cystitis (BPS/IC) is a persistent pain perceived in the urinary bladder region, accompanied by at least one symptom, such as pain worsening with bladder filling and daytime or nighttime urinary frequency without any proven infection or obvious pathology. The aim of this study is to evaluate the efficacy and safety of pentosan polysulfate (PPS) in patients with BPS/IC.
Learn More >For centuries, cannabis and its components have been used to manage a wide variety of symptoms associated with many illnesses. Gastrointestinal (GI) diseases are no exception in this regard. Individuals suffering from inflammatory bowel disease (IBD) are among those who have sought out the ameliorating properties of this plant. As legal limitations of its use have eased, interest has grown from both patients and their providers regarding the potential of cannabis to be used in the clinical setting. Similarly, a growing number of animal and human studies have been undertaken to evaluate the impact of cannabis and cannabinoid signaling elements on the natural history of IBD and its associated complications. There is little clinical evidence supporting the ability of cannabis or related products to treat the GI inflammation underlying these disorders. However, 1 recurring theme from both animal and human studies is that these agents have a significant impact on several IBD-related symptoms, including abdominal pain. In this review, we discuss the role of cannabis and cannabinoid signaling in visceral pain perception, what is currently known regarding the efficacy of cannabis and its derivatives for managing pain, related symptoms and inflammation in IBD, and what work remains to effectively utilize cannabis and its derivatives in the clinical setting.
Learn More >Orofacial pain disorders are predominately experienced by women. Progesterone, a major ovarian hormone, is neuroprotective and antinociceptive. We recently reported that progesterone attenuates estrogen-exacerbated orofacial pain behaviors, yet it remains unclear what anatomical substrate underlies progesterone's activity in the trigeminal system. Progesterone has been reported to exert protective effects through actions at intracellular progesterone receptors (iPR), membrane-progesterone receptors (mPR), or sigma 1 receptors (Sig-1R). Of these, the iPR and Sig-1R have been reported to have a role in pain. Progesterone can also have antinociceptive effects through its metabolite, allopregnanolone. Two enzymes, 5α-reductase and 3α-hydroxysteroid dehydrogenase (3α-HSD), are required for the metabolism of progesterone to allopregnanolone. Both progesterone and allopregnanolone rapidly attenuate pain sensitivity, implicating action of either progesterone at Sig-1R and/or conversion to allopregnanolone which targets GABA receptors. In the present study, we investigated whether Sig-1 Rs are expressed in nociceptors within the trigeminal ganglia of cycling female rats and whether the two enzymes required for progesterone metabolism to allopregnanolone, 5α-reductase and 3α-hydroxysteroid dehydrogenase, are also present. Adult female rats from each stage of the estrous cycle were rapidly decapitated and the trigeminal ganglia collected. Trigeminal ganglia were processed by either fluorescent immunochemistry or western blotting to for visualization and quantification of Sig-1R, 5α-reductase, and 3α-hydroxysteroid dehydrogenase. Here we report that Sig-1Rs and both enzymes involved in progesterone metabolism are highly expressed in a variety of nociceptive sensory neuron populations in the female rat trigeminal ganglia at similar levels across the four stages of the estrous cycle. These data indicate that trigeminal sensory neurons are an anatomical substrate for the reported antinociceptive activity of progesterone via Sig-1R and/or conversion to allopregnanolone.
Learn More >Chronic headache conditions are characterized by persistent sensitization of the trigeminal system, which involves dysfunction of descending pain modulation. We previously reported that noninvasive vagus nerve stimulation (nVNS) inhibits trigeminal nociception in models of episodic migraine through a mechanism involving enhanced serotonergic and GABAergic descending pain signaling.
Learn More >Biased agonism at G protein-coupled receptors describes the phenomenon whereby some drugs can activate some downstream signaling activities to the relative exclusion of others. Descriptions of biased agonism focusing on the differential engagement of G proteins versus β-arrestins are commonly limited by the small response windows obtained in pathways that are not amplified or are less effectively coupled to receptor engagement, such as β-arrestin recruitment. At the μ-opioid receptor (MOR), G protein-biased ligands have been proposed to induce less constipation and respiratory depressant side effects than opioids commonly used to treat pain. However, it is unclear whether these improved safety profiles are due to a reduction in β-arrestin-mediated signaling or, alternatively, to their low intrinsic efficacy in all signaling pathways. Here, we systematically evaluated the most recent and promising MOR-biased ligands and assessed their pharmacological profile against existing opioid analgesics in assays not confounded by limited signal windows. We found that oliceridine, PZM21, and SR-17018 had low intrinsic efficacy. We also demonstrated a strong correlation between measures of efficacy for receptor activation, G protein coupling, and β-arrestin recruitment for all tested ligands. By measuring the antinociceptive and respiratory depressant effects of these ligands, we showed that the low intrinsic efficacy of opioid ligands can explain an improved side effect profile. Our results suggest a possible alternative mechanism underlying the improved therapeutic windows described for new opioid ligands, which should be taken into account for future descriptions of ligand action at this important therapeutic target.
Learn More >Persistent pain after lumbar surgery (failed back surgery syndrome (FBSS)) remains a leading indication for chronic analgesia. However, no analgesics have proven efficacious for this condition. Although trials have evaluated gabapentinoids for chronic low back pain, none of these trials focused solely on FBSS. This randomized, double-blind cross-over trial evaluated the efficacy of gabapentin (1800mg/day) for FBSS. Eligible patients had a diagnosis of FBBS, an average daily pain score of at least 4 out of 10, a neuropathic pain component (indicated by the PainDetect), and reported at least half of their pain radiating in their lower extremity. Participants were randomized to 2, 7-week study periods separated by a 10-day washout. The primary outcome measure was a 0 – 10 numeric rating scale (NRS) of average pain. Secondary measures included the McGill Pain Questionnaire and Patient Global Impression of Change. The treatment effect was analyzed using a mixed effect analysis of covariance with fixed effects for treatment, period, and baseline 7-day mean NRS pain score and a random effect for participant. The outcome of the model was the mean 7-day NRS score for the last 7 days of each treatment period. Thirty-two participants were randomized and included in the primary analysis; 25 completed both study periods. No difference was detected between treatments on any outcome measure, including the primary (LS mean difference in NRS: -0.01 CI: [-0.22 – 0.20]). Given the escalating rate of complex lumbar surgery, future research to develop novel therapies for this prevalent syndrome are needed.
Learn More >Dependence on opioids and the number of opioid overdose deaths are serious and escalating public health problems, but medication-assisted treatments for opioid addiction remain inadequate for many patients. Glucagon-like pepide-1 (GLP-1) is a gut hormone and neuropeptide with actions in peripheral tissues and in the brain, including regulation of blood glucose and food intake. GLP-1 analogs, which are approved diabetes medications, can reduce the reinforcing and rewarding effects of alcohol, cocaine, amphetamine, and nicotine in rodents. Investigations on effects of GLP-1 analogs on opioid reward and reinforcement have not been reported. We assessed the effects of the GLP-1 receptor agonist Exendin-4 (Ex4) on opioid-related behaviors in male mice, i.e., morphine-conditioned place preference (CPP), intravenous self-administration (IVSA) of the short-acting synthetic opioid remifentanil, naltrexone-precipitated morphine withdrawal, morphine analgesia (male and female mice), and locomotor activity. Ex4 treatment had no effect on morphine-induced CPP, withdrawal, or hyperlocomotion. Ex4 failed to decrease remifentanil self-administration, if anything reinforcing effects of remifentanil appeared increased in Ex4-treated mice relative to saline. Ex4 did not significantly affect analgesia. In contrast, Ex4 dose dependently decreased oral alcohol self-administration, and suppressed spontaneous locomotor activity. Taken together, Ex4 did not attenuate the addiction-related behavioral effects of opioids, indicating that GLP-1 analogs would not be useful medications in the treatment of opioid addiction. This difference between opioids and other drug classes investigated to date may shed light on the mechanism of action of GLP-1 receptor treatment in the addictive effects of alcohol, central stimulants, and nicotine.
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