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In our efforts to identify orally bioavailable CGRP receptor antagonists, we previously discovered a novel series of orally available azepinone derivatives that unfortunately also exhibited the unwanted property of potent time-dependent human CYP3A4 inhibition. Through heterocyclic replacement of the indazole ring, we discovered a series of heterocycle derivatives as high-affinity CGRP receptor antagonists. Some of them showed reasonable oral exposures, and the imidazolone derivatives that showed good oral exposure also exhibited substantially reduced time-dependent CYP3A4 inhibition. Several compounds showed strong in vivo efficacy in our marmoset facial blood flow assay with up to 87% inhibition of CGRP-induced activity. However, oral bioavailability generally remained low, emphasizing the challenges we and others encountered in discovering clinical development candidates for this difficult Class B GPCR target.
Learn More >Acute postoperative pain is associated with adverse short and long-term outcomes among women undergoing surgery for breast cancer. Previous studies identified preexisting pain as a predictor of postoperative pain, but rarely accounted for pain location or chronicity. This study leveraged a multinational pain registry, PAIN OUT, to: (1) characterize patient subgroups based on preexisting chronic breast pain status and (2) determine the association of preexisting chronic pain with acute postoperative pain-related patient-reported outcomes and opioid consumption following breast cancer surgery. The primary outcome was a composite score comprising the mean of pain intensity and pain interference items from the International Pain Outcomes Questionnaire. The secondary outcome was opioid consumption in the recovery room and ward. Among 1889 patients, we characterized three subgroups: no preexisting chronic pain ( = 1600); chronic preexisting pain elsewhere ( = 128) and; chronic preexisting pain in the breast with/without pain elsewhere ( = 161). Controlling for covariates, women with preexisting chronic breast pain experienced more severe acute postoperative pain and pain interference (β = 1.0, 95% CI = 0.7-1.3, < 0.001), and required higher doses of opioids postoperatively (β = 2.7, 95% CI = 0.6-4.8, = 0.013). Preexisting chronic breast pain may be an important risk factor for poor pain-related postoperative outcomes. Targeted intervention of this subgroup may improve recovery.
Learn More >Craniofacial neuropathic pain affects millions of people worldwide and is often difficult to treat. Two key mechanisms underlying this condition are a loss of the negative control exerted by inhibitory interneurons and an early microglial reaction. Basic features of these mechanisms, however, are still poorly understood. Using the chronic constriction injury of the infraorbital nerve (CCI-IoN) model of neuropathic pain in mice, we have examined the changes in the expression of GAD, the synthetic enzyme of GABA, and GlyT2, the membrane transporter of glycine, as well as the microgliosis that occur at early (5 days) and late (21 days) stages post-CCI in the medullary and upper spinal dorsal horn. Our results show that CCI-IoN induces a down-regulation of GAD at both postinjury survival times, uniformly across the superficial laminae. The expression of GlyT2 showed a more discrete and heterogeneous reduction due to the basal presence in lamina III of 'patches' of higher expression, interspersed within a less immunoreactive 'matrix', which showed a more substantial reduction in the expression of GlyT2. These patches coincided with foci lacking any perceptible microglial reaction, which stood out against a more diffuse area of strong microgliosis. These findings may provide clues to better understand the neural mechanisms underlying allodynia in neuropathic pain syndromes.
Learn More >Neuropathic pain is a debilitating condition that is often refractory to treatment. The network of neural substrates for pain transmission and control within the brain is complex and remains poorly understood. Through a combination of neuronal tracing, optogenetics, chemogenetics, electrophysiological recordings, and behavioral assessment, we demonstrate that activation of layer 5 pyramidal neurons in the ventrolateral orbitofrontal cortex (vlOFC) attenuates mechanical and thermal hypersensitivity and cold allodynia in mice with neuropathic pain induced by spared nerve injury (SNI). These vlOFC output neurons project to the posterior ventrolateral periaqueductal gray (vlPAG) region and receive inputs from the ventromedial thalamus (VM). Specific optogenetic and chemogenetic activation of the vlOFC-vlPAG and the VM-vlOFC circuits inhibits hypersensitivity associated with neuropathy. Thus, we reveal a modulatory role of the vlOFC and its projections to the vlPAG circuit in the processing of hypersensitive nociception.
Learn More >The chemokine CC motif ligand 1 (CCL1) participates in immune cell recruitment and, as for other chemokines, is also involved in nociceptive processing. In contrast with previous reports indicating its participation in allodynia and cold hypernociception when spinally administered, its ability to evoke heat thermal analgesia, mediated by circulating leukocytes and endocannabinoids, after systemic administration has recently been reported. Aiming to explore the possible role played by CCL1 on spinal nociception, we study here the effect of its intrathecal administration on thermal nociception in mice. The intrathecal administration of CCL1 (0.3-30 ng) produced dose-dependent analgesia as measured by the unilateral hot plate test. This analgesia evoked by CCL1 peaked 1 h after injection, was prevented by the CCR8 antagonist R243 and was accompanied by a reduction of c-Fos protein expression in dorsal horn spinal neurons. Blood leukocyte depletion did not modify CCL1-evoked analgesic responses that, in contrast, were abolished by the microglial inhibitor minocycline, but not the astroglial inhibitor aminoadipate, suggesting the involvement of spinal microglial cells. Furthermore, analgesia remained unmodified by the coadministration of cannabinoid type 1 or 2 receptors antagonists (AM251 or SR144285). However, it was reversed by naloxone but not by cyprodime or naltrindole (selective antagonists of mu- or delta- opioid receptors). The inhibitory effect induced by the selective kappa-opioid receptor antagonist, nor-binaltorphimine, and by an anti-dynorphin A 1-17 antibody indicates that analgesia evoked by spinal CCL1 is mediated by endogenous dynorphins acting on kappa-opioid receptors. Endogenous dynorphin and microglia behave as key players in heat thermal analgesia evoked by spinal CCL1 in mice.
Learn More >The US opioid epidemic has prompted dramatic changes in public attitudes and regulations governing opioid prescribing. Little is known about the experiences of patients with advanced cancer using opioids in the context of the epidemic.
Learn More >Musculoskeletal (MSK) pain conditions are a leading cause of pain and disability internationally and a common reason to seek health care. Accurate prediction of recurrence for health care seeking due to MSK conditions could allow for better tailoring of treatment. The aim of this project was to characterize patterns of recurrent physical therapy seeking for MSK pain conditions and to develop a preliminary prediction model to identify those at increased risk for recurrent care seeking.
Learn More >The underlying mechanisms for shoulder pain (SP) are still widely unknown. Previous reviews report signs of altered pain processing in SP measured using quantitative sensory testing (QST). Evidence suggests that QST might hold predictive value for SP after intervention, yet it is not known whether QST profiles can be modulated in response to different treatments. Therefore, this systematic review and meta-analysis aimed to assess if QST-parameters can be modified by interventions for patients with SP.
Learn More >To identify the prevalence of neuropathic pain after lower limb fracture surgery, assess associations with pain severity, quality of life and disability, and determine baseline predictors of chronic neuropathic pain at three and at six months post-injury.
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