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To estimate the baseline rates of vascular events among people with migraine.
Learn More >Preclinical studies have reported that sigma-1 receptor antagonists may have efficacy in neuropathic pain states. The sigma-1 receptor is a unique ligand-operated chaperone present in crucial areas for pain control, in both the peripheral and central nervous system. This study assesses the synergistic antihyperalgesic and antiallodynic effect of haloperidol, a sigma-1 antagonist, combined with gabapentin in rats with peripheral neuropathy. Wistar rats male were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of gabapentin and the sigma-1 receptor antagonist, haloperidol, were examined at 11 days post-CCI surgery. An analysis of Surface of Synergistic Interaction was used to determine whether the combination's effects were synergistic. Twelve combinations showed various degrees of interaction in the antihyperalgesic and antiallodynic effects. In hyperalgesia, three combinations showed additive effects, four combinations showed supra-additive effects, and three combinations produced an effect limited by the maximum effect. In allodynia, five combinations showed additive effects, two combinations showed supra-additive effects, and five combinations produced antihyperalgesic effects limited by the maximum effect. These findings indicate that the administration of some specific combination of gabapentin and haloperidol can synergistically reduce nerve injury-induced allodynia and hyperalgesia. This suggests that the haloperidol-gabapentin combination can improve the antiallodynic and antihyperalgesic effects in a neuropathic pain model.
Learn More >The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.
Learn More >Among the opioid receptors, the kappa opioid receptor (KOR) has been gaining substantial attention as a promising molecular target for the treatment of numerous human disorders, including pain, pruritus, affective disorders (i.e., depression and anxiety), drug addiction, and neurological diseases (i.e., epilepsy). Particularly, the knowledge that activation of the KOR, opposite to the mu opioid receptor (MOR), does not produce euphoria or leads to respiratory depression or overdose, has stimulated the interest in discovering ligands targeting the KOR as novel pharmacotherapeutics. However, the KOR mediates the negative side effects of dysphoria/aversion, sedation, and psychotomimesis, with the therapeutic promise of biased agonism (i.e., selective activation of beneficial over deleterious signaling pathways) for designing safer KOR therapeutics without the liabilities of conventional KOR agonists. In this review, the development of new KOR ligands from the class of diphenethylamines is presented. Specifically, we describe the design strategies, synthesis, and pharmacological activities of differently substituted diphenethylamines, where structure-activity relationships have been extensively studied. Ligands with distinct profiles as potent and selective agonists, G protein-biased agonists, and selective antagonists, and their potential use as therapeutic agents (i.e., pain treatment) and research tools are described.
Learn More >Validated diagnostic tools to diagnose chronic neuropathic and mixed pain in children are missing. Therapeutic options are often derived from therapeutics for adults. To investigate the international practice amongst practitioners for the diagnosis and treatment of chronic, neuropathic pain in children and adolescents, we performed a survey study among members of learned societies or groups whose members are known to treat pediatric pain. The survey included questions concerning practitioners and practice characteristics, assessment and diagnosis, treatment and medication. We analyzed 117 returned questionnaires, of which 41 (35%) were fully completed and 76 (65%) were partially completed. Most respondents based the diagnosis of neuropathic pain on physical examination (68 (58.1%)), patient history (67 (57.3%)), and underlying disease (59 (50.4%)) combined. Gabapentin, amitriptyline, and pregabalin were the first-choice treatments for moderate neuropathic pain. Tramadol, ibuprofen, amitriptyline, and paracetamol were the first-choice treatments for moderate mixed pain. Consensus on the diagnostic process of neuropathic pain in children and adolescents is lacking. Drug treatment varies widely for moderate, severe neuropathic, and mixed pain. Hence, diagnostic tools and therapy need to be harmonized and validated for use in children.
Learn More >To compare the effectiveness of different physical exercise interventions for chronic non-specific neck pain.
Learn More >Accurate and up-to-date estimates on incidence, prevalence, mortality, and disability-adjusted life-years (burden) of neurological disorders are the backbone of evidence-based health care planning and resource allocation for these disorders. It appears that no such estimates have been reported at the state level for the US.
Learn More >Both childhood abuse and chronic pain are common in people with substance use disorders (SUDs). Studies have found that exposure to childhood abuse is associated with chronic pain in adulthood; however, few studies have examined this association in people with SUDs. This study aimed to characterize the association between childhood abuse and chronic pain presence and severity in adults with SUDs. Data were obtained from 672 treatment-seeking participants with SUDs on an inpatient detoxification unit. Regression models evaluated whether childhood physical or sexual abuse was associated with the likelihood of chronic pain and severity of several pain-related characteristics: pain catastrophizing, pain severity, and pain interference. Childhood physical and sexual abuse were significantly associated with a greater likelihood of chronic pain in adulthood. In the adjusted analyses, childhood physical abuse was associated with worse pain severity, whereas childhood sexual abuse was associated with greater pain catastrophizing and worse pain interference. Childhood physical and sexual abuse were associated with a greater likelihood of chronic pain in adults with SUDs. Among those with chronic pain, exposure to childhood abuse was associated with a more severe symptom profile, characterized by greater pain severity, more catastrophic interpretations of pain, and more pain-related interference with daily life. People with SUDs and a history of childhood abuse may benefit from screening for pain and interventions to reduce pain catastrophizing. These findings highlight the importance of longitudinal research to understand mechanisms linking childhood abuse exposure to later pain and substance misuse.
Learn More >Adaptive interactions with the environment require optimal integration and segregation of sensory information. Yet, temporal misalignments in the presentation of visual and auditory stimuli may generate illusory phenomena such as the sound-induced flash illusion, in which a single flash paired with multiple auditory stimuli induces the perception of multiple illusory flashes. This phenomenon has been shown to be robust and resistant to feedback training. According to a Bayesian account, this is due to a statistically optimal combination of the signals operated by the nervous system. From this perspective, individual susceptibility to the illusion might be moulded through prolonged experience. For example, repeated exposure to the illusion and prolonged training sessions partially impact on the reported illusion. Therefore, extensive and immersive audio-visual experience, such as first-person shooter videogames, should sharpen individual capacity to correctly integrate multisensory information over time, leading to more veridical perception. We tested this hypothesis by comparing the temporal profile of the sound-induced illusion in a group of expert first-person shooter gamers and a non-players group. In line with the hypotheses, gamers experience significantly narrower windows of illusion (~87 ms) relative to non-players (~105 ms), leading to higher veridical reports in gamers (~68%) relative to non-players (~59%). Moreover, according to recent literature, we tested whether audio-visual intensive training in gamers could be related to the incidence of migraine, and found that its severity may be directly proportioned to the time spent on videogames. Overall, these results suggest that continued training within audio-visual environments such as first-person shooter videogames improves temporal discrimination and sensory integration. This finding may pave the way for future therapeutic strategies based on self-administered multisensory training. On the other hand, the impact of intensive training on visual-related stress disorders, such as migraine incidence, should be taken into account as a risk factor during therapeutic planning.
Learn More >The patient acceptable symptom state (PASS) is a treatment-response criterion developed to determine the clinical relevance of a treatment effect. Its estimates for some patient-reported outcomes (PROs) in non-specific chronic low back pain (cLBP) are lacking and the stability of PRO estimates between independent cLBP populations is unknown. We hypothesized that these PRO estimates will be stable.
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