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The objective of this investigation was to examine the distribution of galcanezumab and a control immunoglobulin 4 antibody containing the same constant regions as galcanezumab, into peripheral and central tissues.
Learn More >To provide evidence-based recommendations for the acute symptomatic treatment of children and adolescents with migraine.
Learn More >Calcitonin gene-related peptide has emerged as a therapeutic target in migraine. Monoclonal antibodies and small molecule receptor antagonists (gepants) directed against CGRP have been approved or are in Phase II or III clinical trials. For monitoring the long-term safety of these drugs, it is helpful to consider the role of CGRP in brain functioning.
Learn More >Previous literature suggests that ketamine may be an effective drug in the palliative care population as this drug has been shown to treat multiple conditions that are common in these patients. This review examines the efficacy of ketamine for the treatment of depression and physical pain in palliative care patients. Eleven studies were included on the topic of ketamine as an antidepressant in the palliative care population. Additionally, 5 RCT studies were included on the topic of physical pain in this population. All 11 studies, including one RCT, found antidepressant effects of ketamine in this patient population. Ketamine's effect on treating physical pain was mixed with the largest and most recent RCTs suggesting no significant analgesic effect. This review suggests that starting qualified patients on intravenous (IV) ketamine and switching to oral or intranasal administration may be the most effective and convenient for treating depression, especially for patients who wish to receive treatment at home. Significant analgesia was found in patients who received epidural or intrathecal ketamine as well as in one study using intravenous administration. More research is necessary to determine which palliative care patients may benefit from ketamine treatment.
Learn More >To provide updated evidence-based recommendations for migraine prevention using pharmacologic treatment with or without cognitive behavioral therapy in the pediatric population.
Learn More >The sphenopalatine ganglion (SPG) has previously been targeted in trigeminal neuralgia (TN), but its role in this condition has not been established.
Learn More >Celecoxib is an NSAID commonly used to treat pain conditions in humans. In addition to its blocking activity on COXs enzymes, several other targets could contribute to its analgesic activity. Here we explore the spinal antinociceptive actions of celecoxib and the potential implication of K7 channels in mediating its effects. Spinal cord in vitro preparations from hind paw-inflamed animals were used to assess the segmental sensory-motor and the early sensory processing of nociceptive information. Electrophysiological recordings of ventral roots and dorsal horn neurones were obtained and the effects of celecoxib and K7 modulators on responses to repetitive dorsal root stimulation at C-fibre intensity were assessed. Celecoxib applied at clinically relevant concentrations produced depressant effects on responses to dorsal root stimulation recorded from both ventral roots and individual dorsal horn neurones, in contrast the non-nociceptive monosynaptic reflex was unaffected. The NSAID indomethacin was devoid of effect on spinal reflexes, but further co-application of celecoxib still produced depressant effects. The depressant actions of celecoxib were abolished after K7 channel blockade and mimicked by its structural analogue dimethyl-celecoxib that lacks COX blocking activity. The present results identify K7 channels as novel central targets for celecoxib that may be relevant to its analgesic effect. This finding contributes to better understand the pharmacology of celecoxib, and reinforces both the role of K7 channels in modulating the excitability of central pain pathways and its validity as target for the design of analgesics. SIGNIFICANCE STATEMENT: N/A.
Learn More >As opioid abuse and addiction have developed into a major national health crisis, prescription of opioids for pain management has become more controversial. However, opioids do help some patients by providing pain relief and improving the quality of life. To better understand the addictive properties of opioids under chronic pain conditions, we used a conditioned place preference (CPP) paradigm to examine the rewarding properties of morphine in rats with persistent nociception.
Learn More >Kappa opioid receptor (KOR) agonists show promise in ameliorating disorders, such as addiction and chronic pain, but are limited by dysphoric and aversive side effects. Clinically beneficial effects of KOR agonists (e.g., analgesia) are predominantly mediated by heterotrimeric G protein signaling, whereas β-arrestin signaling is considered central to their detrimental side effects (e.g., dysphoria/aversion). Here we show that Regulator of G protein Signaling-12 (RGS12), via independent signaling mechanisms, simultaneously attenuates G protein signaling and augments β-arrestin signaling downstream of KOR, exhibiting considerable selectivity in its actions for KOR over other opioid receptors. We previously reported that RGS12-null mice exhibit increased dopamine transporter-mediated dopamine (DA) uptake in the ventral (vSTR), but not dorsal striatum (dSTR), as well as reduced psychostimulant-induced hyperlocomotion; in the current study, we found that these phenotypes are reversed following KOR antagonism. Fast-scan cyclic voltammetry studies of dopamine (DA) release and reuptake suggest that striatal disruptions to KOR-dependent DAergic neurotransmission in RGS12-null mice are restricted to the nucleus accumbens. In both ventral striatal tissue and transfected cells, RGS12 and KOR are seen to interact within a protein complex. Ventral striatal-specific increases in KOR levels and KOR-induced G protein activation are seen in RGS12-null mice, as well as enhanced sensitivity to KOR agonist-induced hypolocomotion and analgesia-G protein signaling-dependent behaviors; a ventral striatal-specific increase in KOR levels was also observed in β-arrestin-2-deficient mice, highlighting the importance of β-arrestin signaling to establishing steady-state KOR levels in this particular brain region. Conversely, RGS12-null mice exhibited attenuated KOR-induced conditioned place aversion (considered a β-arrestin signaling-dependent behavior), consistent with the augmented KOR-mediated β-arrestin signaling seen upon RGS12 over-expression. Collectively, our findings highlight a role for RGS12 as a novel, differential regulator of both G protein-dependent and -independent signaling downstream of KOR activation.
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