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Toll-like receptors (TLR) have been proposed as a site of action that alters opioid pharmacodynamics. However, a comprehensive assessment of acute opioid antinociception, tolerance and withdrawal behaviours in genetic null mutant strains with altered innate immune signalling has not been performed. Nor has the impact of genetic deletion of TLR2/4 on high-affinity opioid receptor binding. Here we show that diminished TLR signalling potentiates acute morphine antinociception equally in male and female mice. However, only male TIR8 null mutant mice showed reduced morphine analgesia. Analgesic tolerance was prevented in TLR2 and TLR4 null mutants, but not MyD88 animals. Withdrawal behaviours were only protected in TLR2 mice. In silico docking simulations revealed opioid ligands bound preferentially to the LPS binding pocket of MD-2 rather than TLR4. There was no binding of [H](-)-naloxone or [H]diprenorphine to TLR4 in the concentrations explored. These data confirm that opioids have high efficacy activity at innate immune pattern recognition binding sites but do not bind to TLR4 and identify critical pathway and sex-specific effects of the complex innate immune signalling contributions to opioid pharmacodynamics. These data further support the behavioural importance of the TLR-opioid interaction but fail to demonstrate direct evidence for high-affinity binding of the TLR4 signalling complex to ligands.
Learn More >The midbrain periaqueductal gray (PAG) is a key structure involved in the supraspinal modulation of pain. Previous studies have reported the association of gut inflammation-triggered chronic abdominal pain with structural and neuronal alterations within the PAG. However, whether PAG-executed visceral nociception processing and descending modulation are altered in gut pathology is not known. We used c-Fos immunohistochemistry and extracellular microelectrode recording in urethane-anesthetized male Wistar rats to evaluate the colitis-induced changes in visceral pain-related neuronal properties of the PAG and its descending outflow to visceral nociceptive neurons of the caudal ventrolateral medulla (CVLM). Analysis of c-Fos protein expression in inflamed animals has shown diminished activation of the lateral and ventrolateral PAG columns by noxious colorectal distension (CRD), although the nonstimulated c-Fos labeling in these PAG subdivisions was enhanced compared with that in controls. Microelectrode recording in the ventrolateral PAG revealed a colitis-elicited decrease in the proportion of CRD-excited neurons accompanied by an increase in the number of unresponsive cells and weakened reactions to the stimulation of CRD-inhibited PAG units. Colonic inflammation has also been found to cause a shift in the effects of ventrolateral PAG electrostimulation on CRD-excited CVLM neurons from being mostly inhibitory under normal conditions to excitatory in colitis. These findings identify impaired PAG functioning in ascending and descending visceral nociception control that may contribute to gut injury-associated visceral hyperalgesia. The data obtained can benefit a better understanding of the supraspinal mechanisms involved in the pathogenesis of postinflammatory chronic abdominal pain.
Learn More >Chemotherapy-induced peripheral neuropathy (CIPN) is a common and debilitating side effect of cancer treatment with no effective preventative strategy or definitive treatment. To synthesize empiric literature from randomized controlled trials (RCTs) of pharmacological and nonpharmacological management of CIPN. Articles published between January 1, 2010, and February 28, 2021, were identified using keywords searching Medline, PubMed, CINAHL, Web of Science, Cochrane Library, and Embase. RCTs that recruited individuals who were post-chemotherapy and experienced persistent CIPN symptoms. Three independent reviewers screened a total of 2023 abstracts. After screening, full-text review, and quality appraisal, 22 articles were included in this review. Data related to study design, participant characteristics, interventions, controls, outcome measures, and relevant findings were extracted from full texts. Descriptive quantitative summaries were calculated and narrative analysis was performed. Of the 22 studies, 4 investigated pharmacologic treatments, 2 compared acupuncture to pharmacologic treatments, and 16 studies examined nonpharmacologic treatments. Pharmacologic studies reported mixed results with evidence of participant response varying by history of chemotherapeutic agent. Acupuncture, exercise/physical therapy, and neurofeedback appear to be effective treatments for CIPN. Evidence regarding biophysical agents and cognitive-behavioral therapy is equivocal. Scrambler therapy is not supported. Studies included in this review share several limitations, including widely variable outcome measures, small and demographically homogenous samples, and nonstandardized treatment protocols. This scoping review summarized the current body of high-quality RCTs investigating treatment for CIPN. The majority of studies in this review reports benefits of pharmacologic and nonpharmacologic interventions, although management may require a multipronged approach and should be tailored to the individual. Clinical implications are proposed and suggestions made for future research include implementation of standardized intervention protocols, use of outcome measures representative of the spectrum of CIPN symptoms, and stratification by the chemotherapeutic agent.
Learn More >Opioids are an important therapeutic option for severe resistant chronic pain but, in the absence of proper oversight, their use has risks. The level of prescription opioid misuse/abuse differs among countries, due to differences in healthcare systems and pain management approaches. However, evaluating the true dimension of prescription opioid misuse/abuse is complicated by statistical reporting which often does not differentiate between prescription and illicit opioid use, or between prescription opioid use by patients and nonpatients, highlighting a need for greater uniformity. Parallel efforts to educate patients and the general public about opioid risks, facilitate appropriate analgesic prescribing and identify alternative formulations or options to use instead of or with opioids, may contribute to optimizing prescription opioid use for pain management.
Learn More >Rheumatoid arthritis (RA) is a common systemic inflammatory autoimmune disease that severely affects the life quality of patients. Current therapeutics in clinic mainly focus on alleviating the development of RA or relieving the pain of patients. The emerging biological disease-modifying antirheumatic drugs (DMARDs) require long-term treatment to achieve the expected efficacy. With the development of bionanotechnology, nucleic acids fulfill characters as therapeutics or nanocarriers and can therefore be alternatives to combat RA. This review summarizes the therapeutic RNAs developed through RNA interference (RNAi), nucleic acid aptamers, DNA nanostructures-based drug delivery systems, and nucleic acid vaccines for the applications in RA therapy and diagnosis. Furthermore, prospects of nucleic acids for RA therapy are intensively discussed as well.
Learn More >Stress has been shown to affect brain activity and exert potent and complex modulatory effects on pain. Several behavioral tests have shown that acute stress produces hyperalgesia, depending on the stress conditions. In the present study, we investigated the effects of single restraint stress on the tactile threshold and anxiety sensitivity in mice. Mice were evaluated for the tactile threshold using von Frey filaments and for anxiety sensitivity using the elevated plus maze (EPM) test. Tactile thresholds were lowered by both 2 and 4 hour of restraint stress, but anxiety-like behaviors were observed only after 4 hour of restraint stress in the EPM test. In addition, we found that alfaxalone, which is a positive allosteric modulator of the γ-aminobutyric acid (GABA) receptor, prevented restraint stress-induced hyperalgesia-like and anxiety-like behaviors. These results indicate that GABAergic function appears to be critical in the regulation of physical stress-induced hyperalgesia and anxiety.
Learn More >Chronic pain is associated with insomnia. The objective of this clinical study is to compare the efficacy and safety of different prescribed doses of zopiclone and clonidine; for the management of insomnia in patients with chronic pain.
Learn More >Contrary to pre-attack symptoms before an individual cluster headache attack, little is known about the pre-cluster symptoms before the onset of cluster bouts. We previously described pre-attack symptoms before cluster headache attacks. The aim of this study was to investigate characteristics of pre-cluster symptoms in patients with episodic cluster headache.
Learn More >Cluster headache (CH) is a severe trigeminal autonomic cephalalgia that, when refractory to medical treatment, can be treated with Gamma Knife radiosurgery (GKRS). The outcomes of studies investigating GKRS for CH in the literature are inconsistent, and the ideal target and treatment parameters remain unclear. The aim of this systematic review is to evaluate the safety and the efficacy, both short and long term, of GKRS for the treatment of drug-resistant CH. A systematic review of the literature was performed to identify all clinical articles discussing GKRS for the treatment of CH. The literature review revealed 5 studies describing outcomes of GKRS for the treatment of CH for a total of 52 patients (48 included in the outcome analysis). The trigeminal nerve, the sphenopalatine ganglion, and a combination of both were treated in 34, 1, and 13 patients. The individual studies demonstrated initial meaningful pain reduction in 60-100% of patients, with an aggregate initial meaningful pain reduction in 37 patients (77%). This effect persisted in 20 patients (42%) at last follow-up. Trigeminal sensory disturbances were observed in 28 patients (58%) and deafferentation pain in 3 patients (6%). Information related to GKRS for CH are limited to few small open-label studies using heterogeneous operative techniques. In this setting, short-term pain reduction rates are high, whereas the long-term results are controversial. GKRS targeted on the trigeminal nerve or sphenopalatine ganglion is associated to a frequent risk of trigeminal disturbances and possibly deafferentation pain.
Learn More >The goal of the present study was to comparatively analyze Social Cognition skills in a pediatric population diagnosed with Migraine or Epilepsy, compared to Typically Developing children (TD). The secondary aim was to relate Social Cognition skills with other migraine- or epilepsy-related variables and with executive and cognitive functions.
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