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ETAR and protein kinase A pathway mediate ET-1 sensitization of TRPA1 channel: a molecular mechanism of ET-1-induced mechanical hyperalgesia.

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The Etiological Contribution of GABAergic Plasticity to the Pathogenesis of Neuropathic Pain.

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Sustained Relief of Trigeminal Neuropathic Pain by a BBB Penetrable PPAR Gamma Agonist.

The blood-brain (BBB) and blood-nerve barriers ensure protection of the nervous system but pose a challenge for treatment of pain since it restricts passage of many therapeutic drugs. Although it is unknown which blood-neural barrier is more relevant, or whether permeabilities are the same for different barriers, we proposed that the inefficiency of thioglitazone type agonists for peroxisome proliferator-activated receptor gamma (PPARɣ) is due to their difficulty in passage through the BBB. We developed a new highly BBB penetrable PPARɣ agonist for the treatment of neuropathic pain, assuming BBB permeability is a rule of thumb to estimate the overall permeability of relevant blood-neural barriers. The peak ELB00824/ pioglitazone concentration (Cmax) in the brain was 5.4 versus 0.2 µM in blood at equivalent doses (10 mg/kg i.p.). The series of studies presented here indicate that ELB00824 may be the most potent PPARɣ agonist currently known for acute reduction of neuropathic pain in trigeminal nerve in rat and mouse models. Low dose PPARɣ agonist, ELB00824 (10 mg/kg), effectively decreased neuropathic hypersensitivity in mice and rats at both acute and chronic time points, a dose 100-fold lower than the effective dose (1000 mg/kg, i.p.) of pioglitazone. Comparisons of ELB00824 alone or in combination with gabapentin or carbamazepine are provided. While PPARɣ agonists used to treat Type 2 diabetes produce several adverse side effects, sub-chronic oral toxicity study provided promising results that ELB00824 does not produce any significant short-term toxicity. The study animals of either sex remained alive and healthy with no significant alteration of body weight long-term. Toxicity study results obtained were satisfactory, with no significant alterations in any serum biochemistry parameters.

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Monosodium iodoacetate-induced monoarthritis develops differently in knee versus ankle joint in rats.

Disability and movement-related pain are major symptoms of joint disease, motivating the development of methods to quantify motor behaviour in rodent joint pain models. We compared effects on behaviour, assessed the levels of biochemical mediators and made a detailed histopathological evaluation after induction of rat monoiodoacetate (MIA) monoarthritis into the ankle or knee joint.

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Spinal microglia contribute to cancer-induced pain through system xC−-mediated glutamate release.

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NPY2R signaling gates spontaneous and mechanical, but not thermal, pain transmission.

Neuropeptide Y (NPY) signaling plays an important role in inhibiting chronic pain in the spinal cord of mice. However, little is known about the respective roles of two major NPY receptors, Y1R and Y2R, in evoked, and spontaneous, pain behavior under normal physiological condition. Using intrathecal (i.t.) administration approach, we found that pharmacological inhibition of Y2R, unexpectedly, gave rise to spontaneous pain behavior. In addition, Y2R antagonism also resulted in long-lasting mechanical but not thermal hypersensitivity. By contrast, no overt spontaneous pain behavior, nor mechanical and thermal hypersensitivity were detected after pharmacological inhibition of Y1R. Remarkably, activation of Y1R produced powerful analgesic effect: blocking both evoked and spontaneous pain behavior resulted from Y2R antagonism. These findings highlight the pivotal role of endogenous Y2R in gating mechanical and spontaneous pain transmission. Importantly, our results suggest that Y1R could be a therapeutic target that may be exploited for alleviating spontaneous pain without affecting acute pain transmission.

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Dorsal Root Ganglia Homeobox downregulation in primary sensory neurons contributes to neuropathic pain in rats.

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Brain networks and endogenous pain inhibition are modulated by age and sex in healthy rats.

Endogenous pain inhibition is less efficient in chronic pain patients. Diffuse noxious inhibitory control (DNIC), a form of endogenous pain inhibition, is compromised in women and older people, making them more vulnerable to chronic pain. However, the underlying mechanisms remain unclear. Here, we used a capsaicin-induced DNIC test and resting state functional MRI to investigate the impact of aging and sex on endogenous pain inhibition and associated brain circuitries in healthy rats. We found that DNIC was less efficient in young females compared to young males. DNIC response was lost in old rats of both sexes, but the brain networks engaged during DNIC differed in a sex-dependent manner. Young males had the most efficient analgesia with the strongest connectivity between anterior cingulate cortex (ACC) and periaqueductal gray (PAG). The reduced efficiency of DNIC in young females appeared to be driven by a widespread brain connectivity. Old males showed increased connectivity between PAG, raphe nuclei, pontine reticular nucleus and hippocampus, which may not be dependent on connections to ACC, while old females showed increased connectivity between ACC, PAG and more limbic regions. These findings suggest that distinct brain circuitries including the limbic system may contribute to higher susceptibility to pain modulatory deficits in the elderly population, and sex may be a risk factor for developing age-related chronic pain.

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Effects of oxycodone and diazepam alone and in combination on operant nociception.

Developing effective analgesics with fewer unwanted side effects is a pressing concern. Due to a lack of effective nonopioid options currently available, an alternative approach termed opioid-sparing evaluates the ability of a coadministered drug to reduce the amount of opioid needed to produce an antinociceptive effect. Opioids and benzodiazepines are often coprescribed. Although this approach is theoretically rational given the prevalent comorbidity of chronic pain and anxiety, it also has inherent risks of respiratory depression, which is likely responsible for the substantial percentage of fatal opioid overdoses that have involved benzodiazepines. Moreover, there have been no clinical trials to support the effectiveness of this drug combination nor has there been corroborative preclinical evidence using traditional animal models of nociception. The present studies examined the prescription µ-opioid analgesic oxycodone (0.003-0.1 mg/kg) and the prototypical benzodiazepine anxiolytic diazepam (0.03-1.0 mg/kg), alone and in combination, using an animal model of pain that examines the restoration of conflict-related operant behavior as evidence of analgesia. Results documented significant dose-related increases in thermal threshold following oxycodone treatment. Diazepam treatment alone did not produce significant antinociception. In combination, diazepam pretreatment shifted oxycodone functions upward in a dose-dependent manner, but the additive effects were limited to a narrow dose range. In addition, combinations of diazepam and oxycodone at higher doses abolished responding. Taken together, though intriguing, these findings do not provide sufficient evidence that coadministration of an anxiolytic will result in clinically relevant opioid-sparing for pain management, especially when considering the inherent risks of this drug class combination.

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Activation of Different Heterodimers of TLR2 Distinctly Mediates Pain and Itch.

Toll-like receptors (TLRs) have been implicated in pain and itch regulation. TLR2, a TLR family member that detects microbial membrane components, has been implicated in pathologic pain. However, the role of TLR2 in pruritic and nociceptive responses has not been thoroughly investigated. In this study, we found that TLR2 was expressed in mouse dorsal root ganglia (DRG) and trigeminal ganglia (TG) neurons. Itch and pain behaviors, including histamine-dependent and histamine-independent acute itching, acetone/diethyl ether/water and 2,4-dinitrofluorobenzene-induced chronic itching and inflammatory pain, were largely attenuated in TLR2 knockout (KO) mice. The TLR2 agonist Pam3CSK4, which targets TLR2/1 heterodimers, evoked pain and itch behavior, whereas lipoteichoic acid (LTA) and zymosan, which recognize TLR2/6 heterodimers, produced only pain response. The TLR2 agonist-induced nociceptive and pruritic behaviors were largely diminished in transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) KO mice. Finally, Pam3Csk4 and zymosan increased the [Ca2] in DRG neurons from wild-type mice. However, the enhancement of [Ca2] was largely inhibited in the DRG neurons from TRPV1 and TRPA1 KO mice. Our results demonstrate that TLR2 is involved in different itch and pain behaviors through activating TLR1/TLR2 or TLR6/TLR2 heterodimers via TRPV1 and TRPA1 channels.

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