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Abstract: Chronic pain is a significant public health problem with a lack of safe and effective analgesics. The imidazoline I2 receptor (I2R) is a promising analgesic target, but the neuroanatomical structures involved in mediating I2R‐associated behaviors are unknown. I2Rs are enriched in the arcuate nucleus, dorsal raphe (DR), interpeduncular nucleus, lateral mammillary body, medial habenula, nucleus accumbens (NAc) and paraventricular nucleus; thus, this study investigated the antinociceptive and hypothermic effects of microinjections of the I2R agonist 2‐(2‐benzofuranyl)‐2‐imidazoline hydrochloride (2‐BFI). In rats, intra‐DR microinjections produced antinociception in complete Freund's adjuvant‐ and chronic constriction injury‐induced pain models. Intra‐NAc microinjections produced antinociception and increased noxious stimulus‐associated side time in a place escape/avoidance paradigm. Intra‐NAc pretreatment with the I2R antagonist idazoxan but not the D1 receptor antagonist SCH23390 or the D2 receptor antagonist raclopride attenuated intra‐NAc 2‐BFI‐induced antinociception. Intra‐NAc idazoxan did not attenuate systemically administered 2‐BFI‐induced antinociception. Microinjections into the other regions did not produce antinociception, and in none of the regions produced hypothermia. These data suggest that I2R activation in some but not all I2R‐enriched brain regions is sufficient to produce antinociception and supports the theory that different I2R‐associated effects are mediated via distinct receptor populations, which may in turn be distributed differentially throughout the CNS. [ABSTRACT FROM AUTHOR]

Interleukin-17 (IL-17) is considered to play an important role in the pathogenesis of a number of inflammatory conditions. Previous studies demonstrated that intranasal injections of IL-17 resulted in pulmonary inflammation and lung damage, we therefore hypothesize that dexmedetomidine, a potent α2 adrenergic receptor agonist that shows anti-inflammation effects in several animal models of inflammation, would attenuate IL-17 induced lung injury. We examined the lung damage using a histological approach, and assessed the number of lung-infiltrating neutrophils in the bronchoalveolar lavage fluid. We then compared the production of selected cytokines by measuring their serum concentration after various treatments. Finally, we evaluated the expression of selected inflammatory genes and activation of NF-κB in the lung epithelial cells, using real-time PCR and western blot assay, respectively. In every aspect of pulmonary inflammation investigated, dexmedetomidine significantly and dose-dependently attenuated the inflammatory effects of IL-17. Our results not only give a comprehensive description of the protective action of dexmedetomidine on IL-17 induced acute lung injury, but also provide insights to the underlying cellular and molecular mechanisms. [ABSTRACT FROM AUTHOR]

Chronic pain remains a challenging clinical reality, yet currently available analgesics are insufficient to meet clinical needs. Increasing attention has been paid to bioactive compounds from natural plants, which may be efficacious against pain. This study examined the antinociceptive effects of isosakuranetin, a plant-derived transient receptor potential melastatin 3 blocker, in a rat model of peripheral neuropathy. Adult male Sprague-Dawley rats were first allowed to go through the chronic constriction injury surgery to develop neuropathic pain. They were then treated with isosakuranetin (1.5, 3, or 6 mg/kg) intraperitoneally and the effects on mechanical, thermal, and cold hyperalgesia were assessed using the von Frey filament test, Hargreaves' plantar test, and cold plate test, respectively. Isosakuranetin dose-dependently alleviated mechanical, thermal, and cold hyperalgesia and the antinociceptive potency was similar across the assays. In the rotarod test, isosakuranetin did not significantly affect motor performance within the doses tested, confirming the antinociceptive specificity. In summary, these findings suggest that isosakuranetin may be useful in treating neuropathic pain and deserves further investigation. [ABSTRACT FROM AUTHOR]

Paclitaxel-induced downregulation of two-pore domain K+ channel 1.1 (K 2p 1.1) caused by increasing DNA methylation within its gene promoter in the dorsal root ganglion (DRG) contributes to neuropathic pain. Given that ten-eleven translocation methylcytosine dioxygenase 1 (TET1) promotes DNA demethylation and gene transcription, the present study investigated whether DRG overexpression of TET1 produces an antinociceptive effect on the paclitaxel-induced nociceptive hypersensitivity. TET1 was overexpressed in the DRG through unilateral microinjection of the herpes simplex virus expressing full-length Tet1 mRNA into the fourth and fifth lumbar DRGs of male rats. Behavioral tests were carried out to examine the effect of this overexpression on the paclitaxel-induced nociceptive hypersensitivity. Western blot analysis, chromatin immunoprecipitation assay and 5-hydroxymethylcytosine detection assay were performed to assess the levels of TET1/K 2p 1.1, 5-methylcytosine and 5-hydroxymethylcytosine, respectively. DRG overexpression of TET1 mitigated the paclitaxel-induced mechanical allodynia, heat hyperalgesia and cold hyperalgesia on the ipsilateral side during the development and maintenance periods. Locomotor function or basal (acute) responses to mechanical, heat or cold stimuli were not affected. Mechanistically, DRG overexpression of TET1 rescued the expression of K 2p 1.1 by blocking the paclitaxel-induced increase in the level of 5-methylcytosine and correspondingly reversing the paclitaxel-induced decreases in the amount of 5-hydroxymethylcytosine within the K 2p 1.1 promoter region in the microinjected DRGs of male rats. Our findings suggest that DRG overexpression of TET1 alleviated chemotherapy-induced neuropathic pain likely through rescuing DRG K 2p 1.1 expression. Our findings may provide a potential avenue for the management of this disorder. [ABSTRACT FROM AUTHOR]

Background: There is growing evidence of a strong correlation between pain sensitivity and cognitive function under both physiological and pathological conditions. However, the detailed mechanisms remain largely unknown. In the current study, we sought to explore candidate genes and common molecular mechanisms underlying pain sensitivity and cognitive function with a transcriptome‐wide association study using recombinant inbred mice from the BXD family. Methods: The pain sensitivity determined by Hargreaves' paw withdrawal test and cognition‐related phenotypes were systematically analyzed in 60 strains of BXD mice and correlated with hippocampus transcriptomes, followed by quantitative trait locus (QTL) mapping and systems genetics analysis. Results: The pain sensitivity showed significant variability across the BXD strains and co‐varies with cognitive traits. Pain sensitivity correlated hippocampual genes showed a significant involvement in cognition‐related pathways, including glutamatergic synapse, and PI3K‐Akt signaling pathway. Moreover, QTL mapping identified a genomic region on chromosome 4, potentially regulating the variation of pain sensitivity. Integrative analysis of expression QTL mapping, correlation analysis, and Bayesian network modeling identified Ring finger protein 20 (Rnf20) as the best candidate. Further pathway analysis indicated that Rnf20 may regulate the expression of pain sensitivity and cognitive function through the PI3K‐Akt signaling pathway, particularly through interactions with genes Ppp2r2b, Ppp2r5c, Col9a3, Met, Rps6, Tnc, and Kras. Conclusions: Our study demonstrated that pain sensitivity is associated with genetic background and Rnf20‐mediated PI3K‐Akt signaling may involve in the regulation of pain sensitivity and cognitive functions. [ABSTRACT FROM AUTHOR]

Metformin is a hypoglycemic drug widely used in the treatment of type 2 diabetes. It has been proven to have analgesic and neuroprotective effects. Metformin can reverse pain in rodents, such as diabetic neuropathic pain, neuropathic pain caused by chemotherapy drugs, inflammatory pain and pain caused by surgical incision. In clinical use, however, metformin is associated with reduced plasma vitamin B12 levels, which can further neuropathy. In rodent diabetes models, metformin plays a neuroprotective and analgesic role by activating adenosine monophosphate‐activated protein kinase, clearing methylgloxal, reducing insulin resistance, and neuroinflammation. This paper also summarized the neurological adverse reactions of metformin in diabetic patients. In addition, whether metformin has sexual dimorphism needs further study. [ABSTRACT FROM AUTHOR]

Background: Nerve injury-induced changes in gene expression in the dorsal root ganglion (DRG) contribute to neuropathic pain genesis. Eukaryotic initiation factor 4 gamma 2 (eIF4G2) is a general repressor of cap-dependent mRNA translation. Whether DRG eIF4G2 participates in nerve injury-induced alternations in gene expression and nociceptive hypersensitivity is unknown.Methods: The expression and distribution of eIF4G2 mRNA and protein in mouse DRG after spinal nerve ligation (SNL) were assessed. Effects of eIF4G2 siRNA microinjected through a glass micropipette into the injured DRG on the SNL-induced DRG mu opioid receptor (MOR) and Kv1.2 downregulation and nociceptive hypersensitivity were examined. In addition, effects of DRG microinjection of adeno-associated virus 5-expressing eIF4G2 (AAV5-eIF4G2) on basal DRG MOR and Kv1.2 expression and nociceptive thresholds were analysed.Results: eIF4G2 protein co-expressed with Kv1.2 and MOR in DRG neurones. Levels of eIF4G2 mRNA (1.7 [0.24] to 2.3 [0.14]-fold of sham, P<0.01) and protein (1.6 [0.14] to 2.5 [0.22]-fold of sham, P<0.01) in injured DRG were time-dependently increased on days 3-14 after SNL. Blocking increased eIF4G2 through microinjection of eIF4G2 siRNA into the injured DRG attenuated SNL-induced downregulation of DRG MOR and Kv1.2 and development and maintenance of nociceptive hypersensitivities. DRG microinjection of AAV5-eIF4G2 reduced DRG MOR and Kv1.2 expression and elicited hypersensitivities to mechanical, heat and cold stimuli in naïve mice.Conclusions: eIF4G2 contributes to neuropathic pain through participation in downregulation of Kv1.2 and MOR in injured DRG and is a potential target for treatment of this disorder. [ABSTRACT FROM AUTHOR]

• TLR7 is upregulated in the injured DRG after peripheral nerve injury. • Blocking this upregulation alleviates neuropathic pain. • Mimicking this upregulation produces neuropathic pain-like symptoms. • TLR7 contributed to neuropathic pain by activating the NF-κB signals in the DRG. Toll like receptor 7 (TLR7) is expressed in neurons of the dorsal root ganglion (DRG), but whether it contributes to neuropathic pain is elusive. We found that peripheral nerve injury caused by ligation of the fourth lumbar (L 4) spinal nerve (SNL) or chronic constriction injury of sciatic nerve led to a significant increase in the expression of TLR7 at mRNA and protein levels in mouse injured DRG. Blocking this increase through microinjection of the adeno-associated virus (AAV) 5 expressing TLR7 shRNA into the ipsilateral L 4 DRG alleviated the SNL-induced mechanical, thermal and cold pain hypersensitivities in both male and female mice. This microinjection also attenuated the SNL-induced increases in the levels of phosphorylated extracellular signal-regulated kinase ½ (p-ERK1/2) and glial fibrillary acidic protein (GFAP) in L 4 dorsal horn on the ipsilateral side during both development and maintenance periods. Conversely, mimicking this increase through microinjection of AAV5 expressing full-length TLR7 into unilateral L 3/4 DRGs led to elevations in the amounts of p-ERK1/2 and GFAP in the dorsal horn, augmented responses to mechanical, thermal and cold stimuli, and induced the spontaneous pain on the ipsilateral side in the absence of SNL. Mechanistically, the increased TLR7 activated the NF-κB signaling pathway through promoting the translocation of p65 into the nucleus and phosphorylation of p65 in the nucleus from the injured DRG neurons. Our findings suggest that DRG TLR7 contributes to neuropathic pain by activating NF-κB in primary sensory neurons. TLR7 may be a potential target for therapeutic treatment of this disorder. [ABSTRACT FROM AUTHOR]