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The use of opioid analgesics is severely limited due to the development of intractable constipation, mediated through activation of mu opioid receptors (MOR) expressed by enteric neurons. The related delta opioid receptor (DOR) is an emerging therapeutic target for chronic pain, depression and anxiety. Whether DOR agonists also promote sustained inhibition of colonic transit is unknown. This study examined acute and chronic tolerance to SNC80 and ARM390, which were full and partial DOR agonists in neural pathways controlling colonic motility, respectively. Excitatory pathways developed acute and chronic tolerance to SNC80, whereas only chronic tolerance developed in inhibitory pathways. Both pathways remained functional after acute or chronic ARM390 exposure. Propagating colonic motor patterns were significantly reduced after acute or chronic SNC80 treatment, but not by ARM390 pre-treatment. These findings demonstrate that SNC80 has a prolonged inhibitory effect on propagating colonic motility. ARM390 had no effect on motor patterns and thus may have fewer gastrointestinal side-effects.
Learn More >NADPH oxidase (NOX2) is an enzyme that induces reactive oxygen species (ROS) and serves as a switch between the pro-inflammatory and neurorestorative microglial/macrophage phenotypes; such changes play an important role in neuropathic pain and motor dysfunction. Increased NOX2 expression after spinal cord injury (SCI) has been reported, and inhibition of NOX2 improves motor function. However, the underlying mechanisms of NOX2 in post-traumatic pain and motor deficit remain unexplored. In the present study, we report that depletion of NOX2 (NOX2) or inhibition of NOX2 using NOX2ds-tat significantly reduced mechanical/thermal cutaneous hypersensitivity and motor dysfunction after moderate contusion SCI at T10 in male mice. Western blot (WB, 3 mm lesion area) and immunohistochemistry (IHC) showed that SCI elevates NOX2 expression predominantly in microglia/macrophages up to 8 weeks post-injury. Deletion of NOX2 significantly reduced CD11b/CD45F4/80 macrophage infiltration at 24h post-injury detected by flow cytometry and 8-OHG ROS production at 8 weeks post-injury by IHC in both lesion area and lumbar enlargement. NOX2 deficiency also altered microglial/macrophage pro-inflammatory and anti-inflammatory balance towards the neurorestorative response. WB analysis showed robust increase of Arginase-1 and YM1 proteins in NOX2 mice. Furthermore, qPCR analysis showed significant up-regulation of anti-inflammatory cytokine IL-10 levels in NOX2 mice, associated with reduced microRNA-155 expression. These findings were confirmed in CD11b microglia/macrophages isolated from spinal cord at 3 days post-injury. Taken together, our data suggest an important role for IL-10/miR-155 pathway in regulating NOX2-mediated SCI-dysfunction. Thus, specific targeting of NOX2 may provide an effective strategy for treating neurological dysfunction in SCI patients.
Learn More >The present study investigated the role of the amygdala NMDA receptors/NOS pathway in morphine-induced anti-allodynia. Concurrently with the bilateral cannulation of the central amygdala (CeA), chronic constriction of the sciatic nerve was performed on male Wistar rats. Morphine (3-5 mg/kg) was intraperitoneally administered to induce anti-allodynia. When D-AP5, a selective NMDA receptor antagonist, (0.05-0.1 µg/rat) or L-NAME, the NO synthase inhibitor, (0.1-0.5 µg/rat) were microinjected into the CeA, the higher doses potentiated an ineffective dose of morphine (3 mg/kg). Microinjection of the same doses of D-AP5 and L-NAME without morphine had no effect. Co-microinjection of the ineffective doses of L-NAME (0.1 µg/rat) and D-AP5 (0.05 µg/rat) with a 5-min interval, enhanced the anti-allodynic effect of morphine (3 mg/kg). Western blot analysis was employed to evaluate the levels of cAMP-response element-binding protein (CREB) and phosphorylated CREB (pCREB) in the amygdala tissues. Our results showed that neuropathic pain increased the pCREB/CREB ratio in the amygdala, while this ratio was decreased following morphine-induced anti-allodynia. The potentiative effect of the co-administration of D-AP5/L-NAME on an ineffective dose of morphine also decreased the amygdala pCREB/CREB levels. Therefore, it seems that the amygdala pCREB/CREB signaling pathway plays a critical role in processing neuropathic pain. Moreover, the glutamate NMDA receptors and NO system in the amygdala may be involved in morphine-induced anti-allodynia. PERSPECTIVE: Neuropathic pain is hard to treat and the exact mechanisms are still unknown. This article suggests the importance of the amygdala glutamatergic and nitric oxide systems in morphine-induced anti-allodynia. The findings might be used in clinical studies to reach a better understanding of neuropathic pain mechanisms and treatment.
Learn More >In this review, we discuss the most recent evidence on mechanisms underlying pathological nociceptive processing in Parkinson's disease patients, as well as novel treatment strategies.
Learn More >The present study's objective is to understand the causal mechanisms underpinning the recovery of individuals with whiplash-associated disorders (WAD). We applied Bayesian Networks (BN) to answer two study aims: (1) to identify the causal mechanism(s) of recovery underpinning neck-specific exercise, and (2) quantify if the cyclical pathway of the fear avoidance model (FAM) is supported by the present data.
Learn More >Neuropathic pain, which presents abnormal pain manifestations including allodynia and hyperalgesia, is associated with central sensitization involving N-methyl-D-aspartate receptorsIn the freeze-injury hyperalgesia model, a cold burn leads to development of both primary hyperalgesia and secondary hyperalgesia, which develops away from the site of injury without apparent tissue modification, and is associated with central sensitization and activation of N-methyl-D-aspartate receptors in the spinal cordDextromethorphan, which is an N-methyl-D-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models WHAT THIS ARTICLE TELLS US THAT IS NEW: Using the freeze-injury pain model in a randomized, double-blind, placebo-controlled crossover trial of 30-mg doses of oral dextromethorphan in 20 male volunteers, dextromethorphan was antihyperalgesic and reversed peripheral and central neuronal sensitizationBecause dextromethorphan had no intrinsic antinociceptive effect in acute pain on healthy skin, N-methyl-D-aspartate receptors may need to be sensitized by pain for dextromethorphan to be effective BACKGROUND:: Central pain sensitization is often refractory to drug treatment. Dextromethorphan, an N-methyl-D-aspartate receptor antagonist, is antihyperalgesic in preclinical pain models. The hypothesis is that dextromethorphan is also antihyperalgesic in humans.
Learn More >Pain is a common nonmotor symptom of Parkinson's disease (PD) that remains neglected and misunderstood. Elucidating the nondopaminergic circuitry may be key to better understanding PD and improving current treatments. We investigated the role of monoamines in nociceptive behavior and descending analgesic circuitry in a rat 6-hydroxydopamine (6-OHDA)-induced PD model and explored the resulting motor dysfunctions and inflammatory responses. Rats pretreated with noradrenaline and serotonin reuptake inhibitors were given unilateral striatal 6-OHDA injections and evaluated for mechanical hyperalgesia and motor impairments. Through immunohistochemistry, the number and activation of neurons, and the staining for astrocytes, microglia and enkephalin were evaluated in specific brain structures and the dorsal horn of the spinal cord. The PD model induced bilateral mechanical hyperalgesia that was prevented by reuptake inhibitors in the paw contralateral to the lesion. Reuptake inhibitors also prevented postural immobility and asymmetric rotational behavior in PD rats without interfering with dopaminergic neuron loss or glial activation in the substantia nigra. However, the inhibitors changed the periaqueductal gray circuitry, protected against neuronal impairment in the locus coeruleus and nucleus raphe magnus, and normalized spinal enkephalin and glial staining in lesioned rats. These data indicate that the preservation of noradrenergic and serotonergic systems regulates motor responses and nociceptive circuitry during PD not by interfering directly with nigral lesions but by modulating the opioid system and glial response in the spinal cord. Taken together, these results suggest that nondopaminergic circuitry is essential to the motor and nonmotor symptoms of PD and must be further investigated.
Learn More >Chronic post-surgical pain after colon surgery in patients included in an enhanced recovery program.
Enhanced recovery after surgery (ERAS) program improves immediate recovery. Beyond immediate benefits, long-term impact of ERAS implementation is not yet evident. This retrospective single-center cohort study investigates prevalence and characteristics of chronic post-surgical pain (CPSP) in patients who underwent colon surgery.
Learn More >Multimodal analgesia is a fundamental part of modern surgery and enhanced recovery pathways. Duloxetine, a serotonin and norepinephrine reuptake inhibitor, has been validated for the treatment of chronic neuropathic pain. The evidence for duloxetine as an adjunct for the treatment of acute postoperative pain remains controversial. We conducted a meta-analysis to determine the efficacy of duloxetine in the acute perioperative setting.
Learn More >Despite growing interest in the role of stress mediators in pain chronicity, the effects of the stress hormone cortisol on acute pain remain incompletely understood. In a randomized, double-blind, placebo-controlled study with N = 100 healthy volunteers, we tested the effects of oral hydrocortisone (20 mg) in 2 widely used pain models for the visceral and somatic modality. Salivary cortisol was increased in the hydrocortisone group (time × group: P < 0.001). For the visceral modality, assessed using pressure-controlled rectal distensions, hydrocortisone decreased the pain threshold from before to after treatment (time × group: P = 0.011), an effect primarily driven by women (time × sex: P = 0.027). For the somatic modality, cutaneous heat pain thresholds remained unaffected by hydrocortisone. Hydrocortisone did not alter perceived pain intensity or unpleasantness of either modality. Conditioned pain-related fear in response to predictive cues was only observed for the visceral modality (time × modality: P = 0.026), an effect that was significantly reduced by hydrocortisone compared with placebo (time × group: P = 0.028). This is the first psychopharmacological study to support that acutely increased cortisol enhances pain sensitivity and impairs pain-related emotional learning within the visceral, but not the somatic pain modality. Stress-induced visceral hyperalgesia and deficits in emotional pain-related learning could play a role in the pathophysiology of chronic visceral pain.
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