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Although tolerance serves as a major limitation in the long-term clinical use of opioids in patients with chronic severe pain, mechanisms of opioid tolerance are poorly understood. In this study, a morphine tolerance model was established by subcutaneously injecting male rats with morphine (10 mg/kg) twice a day for 10 consecutive days. In addition, a subset of morphine-tolerant rats underwent testosterone replacement therapy. The levels of mu-opioid receptor (MOR) mRNA and protein in the trigeminal ganglia (TGs) of morphine-tolerant versus control rats and of morphine-tolerant rats with vs. without testosterone replacement therapy were measured. We found that testosterone levels were significantly lower in morphine-tolerant rats than in the controls (1.248 ± 0.231 ng/ml vs. 2.223 ± 0.153 ng/ ml, respectively; p = 0.008). Furthermore, chronic morphine exposure led to a downregulation in the levels of MOR mRNA to 79.3%, and of MOR protein to 68.9%. Testosterone replacement therapy restored MOR mRNA and protein levels specifically in rats who had developed a tolerance to morphine, thereby suggesting a potential role of testosterone in the opioid-receptor response to chronic morphine exposure. In summary, our study provides evidence for the involvement of testosterone in the proper regulation of the peripheral MOR system in rats following prolonged morphine exposure. We also suggest that analgesic therapeutic measures should take into account the testosterone levels of patients who have built up a tolerance to morphine.
Learn More >The mesopontine tegmental anesthesia area (MPTA) is a small brainstem nucleus that, when exposed to minute quantities of GABA receptor agonists, induces a state of general anesthesia. In addition to immobility and analgesia this state is accompanied by widespread suppression of neural activity in the cerebral cortex and high delta-band power in the electroencephalogram. Collectively, MPTA neurons are known to project to a variety of forebrain targets which are known to relay to the cortex in a highly distributed manner. Here we ask whether ascending projections of individual MPTA neurons collateralize to several of these cortical relay nuclei, or access only one. Using rats, contrasting retrograde tracers were microinjected pairwise on one side into three ascending relays: the basal forebrain, the zona incerta-lateral hypothalamus and the intralaminar thalamic nuclear group. In addition, in separate animals, each target was microinjected bilaterally. MPTA neurons were then identified as being single-or double-labeled, indicating projection to one target nucleus or collateralization to both. Results indicated that double-labeling was rare, occurring on average in only 1.3% of the neurons sampled. The overwhelming majority of individual MPTA neurons showed specific connectivity, contributing to only one of the major ascending pathways, either ipsilaterally or contralaterally, but not bilaterally. This architecture would permit particular functional aspects of anesthetic loss-of-consciousness to be driven by specific subpopulations of MPTA neurons.
Learn More >Limited information on the prevalence and risk factors for chronic pain is available for developing countries. Therefore, we investigated the prevalence of chronic pain, and the association between this pain and various personal and sociodemographic factors by including questions in the South Africa Demographic and Household Survey 2016. The survey was conducted by face-to-face interviews with a nationally representative sample of the adult population (ages 15 and older, n = 10336). Chronic pain was defined as pain or discomfort that had been experienced all the time or on and off for three months or more. The prevalence of chronic pain was 18.3% [95% CI: 17.0, 19.7]. Women were more likely than were men to have chronic pain (Men = 15.8% [95% CI: 13.9, 17.8]; Woman = 20.1% [95% CI: 18.4, 21.8]), and the prevalence of chronic pain increased from 11.3% [95% CI: 9.6, 13.3] for the age range 15-24 years to 34.4% [95% CI: 30.6, 38.4] for the age range over 65 years. The body sites affected most frequently were the limbs (43.6% [95% CI: 40.4, 46.9]), followed by the back (30.5% [95% CI: 27.7, 33.6]). This article presents the prevalence of chronic pain in the general population of a middle-income African country. These data give much needed insights into the burden of, and risk factors for, chronic pain in low-resource settings, and identify priority groups for intervention.
Learn More >Guidelines now discourage opioid analgesics for chronic noncancer pain because the benefits frequently do not outweigh the harms. We aimed to determine the proportion of patients with chronic noncancer pain who are prescribed an opioid, the types prescribed and factors associated with prescribing. Database searches were conducted from inception to 29 October 2018 without language restrictions. We included observational studies of adults with chronic noncancer pain measuring opioid prescribing. Opioids were categorized as weak (e.g. codeine) or strong (e.g. oxycodone). Study quality was assessed using a risk of bias tool designed for observational studies measuring prevalence. Individual study results were pooled using a random-effects model. Meta-regression investigated study-level factors associated with prescribing (e.g. sampling year, geographic region as per World Health Organization). The overall evidence quality was assessed using Grading of Recommendations Assessment, Development and Evaluation criteria. Of the 42 studies (5,059,098 participants) identified, the majority (n = 28) were from the United States of America. Eleven studies were at low risk of bias. The pooled estimate of the proportion of patients with chronic noncancer pain prescribed opioids was 30.7% (95% CI 28.7% to 32.7%, n = 42 studies, moderate-quality evidence). Strong opioids were more frequently prescribed than weak (18.4% (95% CI 16.0-21.0%, n = 15 studies, low-quality evidence), versus 8.5% (95% CI 7.2-9.9%, n = 15 studies, low-quality evidence)). Meta-regression determined that opioid prescribing was associated with year of sampling (more prescribing in recent years) (P = 0.014) and not geographic region (P = 0.056). Opioid prescribing for patients with chronic noncancer pain is common and has increased over time.
Learn More >Human immunodeficiency virus (HIV)-related neuropathic pain includes HIV-induced neuropathic pain (HNP) and antiretroviral therapy-induced neuropathic pain (ART-NP). A significant amount of evidence from the past few years has shown that the development of HIV-related neuropathic pain is closely related to the activation of the Wnt signaling pathway in the spinal cord. This review summarizes the function of the spinal Wnt signaling pathway in HIV-induced neuropathic pain, focusing on the role of the spinal Wnt signaling pathway in HNP, and provides a theoretical basis for further studies and the exploration of new target drugs.
Learn More >The aims of this study were twofold: 1) to better understand the associations between pain-related cognitions and pain severity, and psychological and physical function, and 2) to determine the extent to which these cognitions function as mediators in the association between pain severity and depression in a sample of primary care adult patients with chronic pain and depression.
Learn More >Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with three isoforms (PPARα, PPARβ/δ, PPARγ) and can regulate pain, anxiety, and cognition. However, their role in conditioned fear and pain-fear interactions has not yet been investigated. Here, we investigated the effects of systemically administered PPAR antagonists on formalin-evoked nociceptive behaviour, fear-conditioned analgesia (FCA), and conditioned fear in the presence of nociceptive tone in rats. Twenty-three and a half hours following fear conditioning to context, male Sprague-Dawley rats received an intraplantar injection of formalin and intraperitoneal administration of vehicle, PPARα (GW6471), PPARβ/δ (GSK0660) or PPARγ (GW9662) antagonists, and 30 min later were re-exposed to the conditioning arena for 15 min. The PPAR antagonists did not alter nociceptive behaviour or fear-conditioned analgesia. The PPARα and PPARβ/δ antagonists prolonged context-induced freezing in the presence of nociceptive tone without affecting its initial expression. The PPARγ antagonist potentiated freezing over the entire trial. In conclusion, pharmacological blockade of PPARα and PPARβ/δ in the presence of formalin-evoked nociceptive tone, impaired short-term, within-trial fear-extinction in rats without affecting pain response, while blockade of PPARγ potentiated conditioned fear responding. These results suggest that endogenous signalling through these three PPAR isoforms may reduce the expression of conditioned fear in the presence of nociceptive tone.
Learn More >Whether, how, and which cognitive factors modulate the development of secondary hypersensitivity/hyperalgesia following central sensitization is not fully understood. Here we tested, in three subsequent experiments, whether being engaged in non-pain related cognitive demanding tasks: i) lessens the amount of hypersensitivity developed after an experimental procedure sensitizing nociceptive pathways; ii) modulates cortical responses to somatosensory stimuli (measured by electroencephalography, EEG). In the first experiment we validated a novel model in humans using low frequency stimulation (LFS) of the skin and demonstrated that it was able to successfully induce hypersensitivity to mechanical pinprick stimuli in the area surrounding the sensitized site. In the second and third experiments we engaged participants in tasks of increasing difficulty (the Eriksen Flanker Task in experiment 2, and a modified N-back task in experiment 3). We observed that hypersensitivity to mechanical stimuli still developed in experiment 2, i.e. the pinprick stimuli applied on the sensitized arm were perceived as more intense after LFS. In contrast, no statistically significant enhancement of mechanical hypersensitivity was observed in experiment 3, indicating that, at the group level, being engaged in a difficult N-back task may interfere with the development of mechanical hypersensitivity. Contrary to previous studies, which have used different methods to induce sensitization, we did not observe any increase in the cortical response to somatosensory stimuli applied on the sensitized arm. We conclude that i) the development of pinprick hypersensitivity is modulated by the concomitant execution of a difficult N-back task, and ii) the enhancement of cortical responses to somatosensory stimuli is related to the method used to induce central sensitization.
Learn More >Mechanisms underpinning ongoing symptoms in chronic whiplash associated-disorder (WAD) are not well understood. People with chronic WAD can exhibit sensory dysfunction consistent with small nerve fibre pathology, including thermal hypoaesthesia and hyperalgesia. This study investigated small fibre structure and function in chronic WAD.
Learn More >Central neuropathic pain is a common untreated symptom in progressive multiple sclerosis (PMS) and is associated with poor quality of life and interference with patients' daily activities. The neuroinflammation process and mitochondrial dysfunction in the PMS lesions generate reactive species. The transient potential receptor ankyrin 1 (TRPA1) has been identified as one of the major mechanisms that contribute to neuropathic pain signaling and can be activated by reactive compounds. Thus, the goal of our study was to evaluate the role of spinal TRPA1 in the central neuropathic pain observed in a PMS model in mice. We used C57BL/6 female mice (20-30 g), and the PMS model was induced by the experimental autoimmune encephalomyelitis (EAE) using mouse myelin oligodendrocyte glycoprotein (MOG) antigen and CFA (complete Freund's adjuvant). Mice developed progressive clinical score, with motor impairment observed after 15 days of induction. This model induced mechanical and cold allodynia and heat hyperalgesia which were measured up to 14 days after induction. The hypersensitivity observed was reduced by the administration of selective TRPA1 antagonists (HC-030031 and A-967079, via intrathecal and intragastric), antioxidants (α-lipoic acid and apocynin, via intrathecal and intragastric), and TRPA1 antisense oligonucleotide (via intrathecal). We also observed an increase in TRPA1 mRNA levels, NADPH oxidase activity, and 4-hydroxinonenal (a TRPA1 agonist) levels in spinal cord samples of PMS-EAE induced animals. In conclusion, these results support the hypothesis of the TRPA1 receptor involvement in nociception observed in a PMS-EAE model in mice.
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