Pain
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Although it is clear that osteoarthritis (OA) pain involves activation and/or sensitization of nociceptors that innervate knee joint articular tissues, much less is known about the role of the innervation of surrounding bone. In this study, we used monoiodoacetate (MIA)-induced OA in male rats to test the idea that pain in OA is driven by differential contributions from nerves that innervate knee joint articular tissues vs the surrounding bone. The time-course of pain behavior was assayed using the advanced dynamic weight-bearing device, and histopathology was examined using haematoxylin and eosin histology. ⋯ Changes in the function of bone afferent neurons were only observed at day 28, when there was histological evidence of damage to the articular cartilage and subchondral bone. Our findings suggest that pain early in MIA-induced OA involves activation and sensitization of nerves that innervate the joint capsule but not the underlying subchondral bone, and that pain in late MIA-induced OA involves the additional recruitment of nerves that innervate the subchondral bone. Thus, nerves that innervate bone should be considered important targets for development of mechanism-based therapies to treat pain in late OA.
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A cerebral upregulation of the translocator protein (TSPO), a biomarker of glial activation, has been reported in fibromyalgia subjects (FMS). The TSPO binding affinity is genetically regulated by the Ala147Thr polymorphism in the TSPO gene (rs6971) and allows for a subject classification into high affinity binders (HABs) and mixed/low affinity binders (MLABs). The aim of the present multimodal neuroimaging study was to examine the associations of the TSPO polymorphism with: (1) conditioned pain modulation, (2) expectancy-modulated pain processing assessed during functional magnetic resonance imaging, and (3) the concentration and balance of glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex and thalamus using proton magnetic resonance spectroscopy in FMS (n = 83) and healthy controls (n = 43). ⋯ Translocator protein HABs in both groups (FM and healthy controls) were found to have higher thalamic glutamate concentrations and exhibit a pattern of positive correlations between glutamate and γ-aminobutyric acid in the rostral anterior cingulate cortex, not seen in MLABs. Altogether, our findings point to TSPO-related mechanisms being HAB-dependent, brain region-specific, and non-FM-specific, although in FMS the disadvantage of an aberrant pain regulation combined with an HAB genetic set-up might hamper pain modulation more strongly. Our results provide evidence for an important role of TSPO in pain regulation and brain metabolism, thereby supporting the ongoing drug development targeting TSPO-associated mechanisms for pain relief.
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Data from the Global Burden of Disease Study 2019 were used to report the burden of migraine in 204 countries and territories during the period 1990 to 2019, through a systematic analysis of point prevalence, annual incidence, and years lived with disability (YLD). In 2019, the global age-standardised point prevalence and annual incidence rate of migraine were 14,107.3 (95% Uncertainty Interval [UI] 12,270.3-16,239) and 1142.5 (95% UI 995.9-1289.4) per 100,000, an increase of 1.7% (95% UI 0.7%-2.8%) and 2.1% (95% UI 1.1%-2.8%) since 1990, respectively. Moreover, the global age-standardised YLD rate in 2019 was 525.5 (95% UI 78.8-1194), an increase of 1.5% (95% UI -4.4% to 3.3%) since 1990. ⋯ Belgium (22,400.6 [95% UI: 19,305.2-26,215.8]), Italy (20,337.7 [95% UI: 17,724.7-23,405.8]), and Germany (19,436.4 [95% UI: 16,806.2-22,810.3]) had the 3 highest age-standardised point prevalence rates for migraine in 2019. In conclusion, there were large intercountry differences in the burden of migraine, and this burden increased significantly across the measurement period. These findings suggest that migraine care needs to be included within the health system to increase population awareness regarding the probable risk factors and treatment strategies especially among young adults and middle-aged women, as well as to increase the data on migraines.
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Normalization of the excitatory and inhibitory balance by increasing the levels of endogenous inhibitory neurotransmitters by blocking their reuptake is a promising therapeutic strategy for relieving chronic pain. Pharmacological blockade of spinal γ-aminobutyric acid (GABA) transporter subtypes 1 and 3 (GAT1 and GAT3) has been reported to generate analgesic effects in animal models of neuropathic pain. Here, we explored the synaptic mechanisms underlying their analgesic effects in the spinal dorsal horn. ⋯ These effects were antagonized by the GABAB receptor antagonist CGP55845. Consistently, the analgesic effect of intrathecally injected NNC-711 and SNAP-5114 in mice developing mechanical hypersensitivity after partial sciatic nerve ligation was abolished by CGP55845. Thus, GAT1 and GAT3 inhibitors exert distinct GABAB receptor-mediated inhibitory effects on excitatory synaptic transmission in the spinal dorsal horn, which most likely contributes to their analgesic effects.