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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.
Learn More >Raised extracellular potassium ion (K) concentration is associated with several disorders including migraine, stroke, neurotrauma and epilepsy. K spatial buffering is a well-known mechanism for extracellular K regulation/distribution. Astrocytic gap junction-mediated buffering is a controversial candidate for K spatial buffering. To further investigate the existence of a K spatial buffering and to assess the involvement of astrocytic gap junctional coupling in K redistribution, we hypothesized that neocortical K and concomitant spreading depolarization (SD)-like responses are controlled by powerful local K buffering mechanisms and that K buffering/redistribution occurs partially through gap junctional coupling. Herein, we show, in vivo, that a threshold amount of focally applied KCl is required to trigger local and/or distal K responses, accompanied by a SD-like response. This observation indicates the presence of powerful local K buffering which mediates a rapid return of extracellular K to the baseline. Application of gap junctional blockers, carbenoxolone and Gap27, partially modulated the amplitude and shape of the K response and noticeably decreased the velocity of the spreading K and SD-like responses. Opening of gap junctions by trimethylamine, slightly decreased the amplitude of the K response and markedly increased the velocity of redistribution of K and SD-like events. We conclude that spreading K responses reflect powerful local K buffering mechanisms which are partially modulated by gap junctional communication. Gap junctional coupling mainly affected the velocity of the K and SD-like responses.
Learn More >Postoperative opioid use can lead to chronic use and misuse. Few studies have examined effective approaches to taper postoperative opioid use while maintaining adequate analgesia.
Learn More >To study the characteristics of headache attributed to COVID-19 infection and predictors of its severity.
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