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Rodents are the main model systems for pain research, but determining their pain state is challenging. To develop an objective method to assess pain sensation in mice, we adopt high-speed videography to capture sub-second behavioral features following hind paw stimulation with both noxious and innocuous stimuli and identify several differentiating parameters indicating the affective and reflexive aspects of nociception. Using statistical modeling and machine learning, we integrate these parameters into a single index and create a "mouse pain scale," which allows us to assess pain sensation in a graded manner for each withdrawal. We demonstrate the utility of this method by determining sensations triggered by three different von Frey hairs and optogenetic activation of two different nociceptor populations. Our behavior-based "pain scale" approach will help improve the rigor and reproducibility of using withdrawal reflex assays to assess pain sensation in mice.
Learn More >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.
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