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The dorsal horn of the spinal cord is the first integration site of somatosensory inputs from the periphery. In the superficial layers of the dorsal horn, nociceptive inputs are processed by a complex network of excitatory and inhibitory interneurons whose function and connectivity remain poorly understood. We examined the role of calretinin-expressing interneurons (CR neurons) in such processing and show that they receive direct inputs from nociceptive fibers and polysynaptic inputs from touch-sensitive Aβ fibers. Their activation by chemogenetic or optogenetic stimulation produces mechanical allodynia and nocifensive responses. Furthermore, they monosynaptically engage spinoparabrachial (SPb) neurons in lamina I, suggesting CR neurons modulate one of the major ascending pain pathways of the dorsal horn. In conclusion, we propose a neuronal pathway in which CR neurons are positioned at the junction between nociceptive and innocuous circuits and directly control SPb neurons in lamina I.
Learn More >Trigeminal neuralgia (TN) is characterized by recurrent attacks of lancinating facial pain in the dermatomal distribution of the trigeminal nerve. TN is rare, affecting 4 to 13 people per 100,000.
Learn More >The purpose of this review is to evaluate and summarize recent empirical research investigating motivational factors for management of chronic pain and headache disorders.
Learn More >Deaths associated to tramadol, a synthetic opioid, are rising globally. Herein, we characterize prescription patterns of tramadol relative to other opioids in the USA from 2012 to 2015, by geographic region and physician specialty.
Learn More >MicroRNAs (miRNAs) have been shown to be involved in the pathophysiological processes of pain. At present, the roles and mechanisms of miRNAs in neonatal repetitive pain are largely unknown. In our research, the expression of miR-140-3p was increased in premature infants who received repetitive painful stimuli since admission, and in rat pups after repetitive needlestick stimulation. As a result of behavioral testing, the inhibition of miR-140-3p significantly suppressed abnormal mechanical and thermal hyperalgesia in rats after needlestick. Furthermore, the inhibition decreased the expression of the inflammatory cytokines IL-1β, TNF-α, and IL-6, as well as glucocorticoid receptor expression in rats after needlestick. Using bioinformatic analyses, the 3'-untranslated region of TGF-β3 was predicted to be a target of miR-140-3p. Down-regulation of miR-140-3p significantly promoted the expression of TGF-β3 in vitro and in vivo. Mechanistic investigations revealed that TGF-β3 is a direct target of miR-140-3p, and is involved in the miR-140-3p-mediated effects on neonatal repetitive pain and neuroinflammation. In summary, our current research suggests that down-regulation of miR-140-3p can inhibit painful tactile stimulation of rat pups by inhibiting TGF-β3. Our results suggest that miR-140-3p may provide a new regulatory target for preventing the effects of neonatal repetitive pain.
Learn More >The gasotransmitter hydrogen sulfide (HS) is known to regulate many pathophysiological processes. Preclinical assays have demonstrated that HS donors exhibit anti-inflammatory and antinociceptive activities, characterized by reduction of inflammatory mediators production, leukocytes recruitment, edema and mechanical allodynia. In the present study, the effects induced by 4-methylbenzenecarbothioamide (4-MBC) in models of pain and inflammation in mice, the mechanisms mediating such effects and the HS-releasing property of this compound were evaluated. 4-MBC spontaneously released HS in vitro in the absence of organic thiols. Intraperitoneal (i.p.) administration of 4-MBC (100 or 150 mg/kg) reduced the second phase of the nociceptive response induced by formaldehyde and induced a long lasting inhibitory effect on carrageenan mechanical allodynia. 4-MBC antiallodynic effect was not affected by previous administration of naltrexone or glibenclamide. 4-MBC (50, 100 or 150 mg/kg, i.p.) induced a long lasting inhibitory effect on paw edema induced by carrageenan. The highest dose (150 mg/kg, i.p.) of 4-MBC inhibited tumor necrosis factor-α and CXCL1 production and myeloperoxidase activity induced by carrageenan. Mechanical allodynia and paw edema induced by carrageenan were not inhibited by the 4-MBC oxo analogue (p-toluamide). In summary, 4-MBC, an HS releasing thiobenzamide, exhibits antinociceptive and anti-inflammatory activities. These activities may be due to reduced cytokine and chemokine production and neutrophil recruitment. The HS releasing property is likely essential for 4-MBC activity. Our results indicate that 4-MBC may represent a useful pharmacological tool to investigate the biological roles of HS.
Learn More >Painful diabetic neuropathy (PDN) is a serious symptom that compromises quality of life and remains without effective pharmacological treatment. The transient receptor vanilloid 4 (TRPV4) is a cation-permeable channel implicated in sensory transduction and pain signalling. Therefore, drugs that act on TRPV4 may have therapeutic applications to treat PDN. In the present work, we assessed the effect of the selective TRPV4 channel antagonist HC-067047 on painful neuropathy associated with streptozotocin (STZ)-induced diabetes in mice. STZ-treated animals presented both mechanical and cold allodynia at 6 weeks after diabetes induction. Notably, HC-067047 (1 mg/kg, s.c.) given daily between 2 and 6 weeks after diabetes induction significantly prevented the development of mechanical allodynia. Additionally, both single and repeated treatments with HC-067047 (10 mg/kg, s.c.) significantly reverted established mechanical allodynia induced by STZ. However, HC-067047 was not capable of affecting either thermal cold allodynia or hyperglycemia. Similarly, HC-067047 treatments showed no effect on body weight, temperature, locomotor activity or motor coordination of control mice. Immunohistochemistry assay showed that TRPV4 expression was not different in sciatic nerve, dorsal root ganglia (DRG) or hind paw plantar skin from diabetic and non-diabetic mice, suggesting that HC-067047 acts on constitutive receptors to inhibit mechanical allodynia. Taken together, the data generated in the present study show the potential relevance of using TRPV4 antagonists to treat painful neuropathy associated with diabetes.
Learn More >A trigeminovagal complex, as described in some animals, could help to explain the effect of vagus nerve stimulation as a treatment for headache disorders. However, the existence of a trigeminovagal complex in humans remains unclear. This study, therefore investigated the existence of the trigeminovagal complex in humans. One post-mortem human brainstem was scanned at 11.7T to obtain structural (T1-weighted) and diffusion magnetic resonance images ((d)MR images). Post-processing of dMRI data provided track density imaging (TDI) maps to investigate white matter at a smaller resolution than the imaging resolution. To evaluate the reconstructed tracts, the MR-scanned brainstem and three additional brainstems were sectioned for polarized light imaging (PLI) microscopy. T1-weighted images showed hyperintense vagus medullar striae, coursing towards the dorsomedial aspect of the medulla. dMRI-, TDI- and PLI-images showed these striae to intersect the trigeminal spinal tract (sp5) in the lateral medulla. In addition, PLI images showed that a minority of vagus fibers separated from the vagus trajectory and joined the trigeminal spinal nucleus (Sp5) and the sp5. The course of the vagus tract in the rostral medulla was demonstrated in this study. This study shows that the trigeminal- and vagus systems interconnect anatomically at the level of the rostral medulla where the vagus fibers intersect with the Sp5 and sp5. Physiological and clinical utility of this newly identified interconnection is a topic for further research.
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