Pain
0304-3959
Cơ quản chủ quản: Lippincott Williams and Wilkins Ltd. , LIPPINCOTT WILLIAMS & WILKINS
Lĩnh vực:
NeurologyPharmacologyNeurology (clinical)Anesthesiology and Pain Medicine
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Thông tin về tạp chí
Các bài báo tiêu biểu
Identification of cut-points for mild, moderate and severe pain due to diabetic peripheral neuropathy
Tập 115 - Trang 29-36 - 2005
Selective modulation of tonic aversive qualities of neuropathic pain by morphine in the central nucleus of the amygdala requires endogenous opioid signaling in the anterior cingulate cortex Abstract
The amygdala is a key subcortical region believed to contribute to emotional components of pain. As opioid receptors are found in both the central (CeA) and basolateral (BLA) nuclei of the amygdala, we investigated the effects of morphine microinjection on evoked pain responses, pain-motivated behaviors, dopamine release in the nucleus accumbens (NAc), and descending modulation in rats with left-side spinal nerve ligation (SNL). Morphine administered into the right or left CeA had no effect on nerve injury–induced tactile allodynia or mechanical hyperalgesia. Right, but not left, CeA morphine produced conditioned place preference (CPP) and increased extracellular dopamine in the NAc selectively in SNL rats, suggesting relief of aversive qualities of ongoing pain. In SNL rats, CPP and NAc dopamine release following right CeA morphine was abolished by blocking mu opioid receptor signaling in the rostral anterior cingulate cortex (rACC). Right CeA morphine also significantly restored SNL-induced loss of the diffuse noxious inhibitory controls, a spino-bulbo-spinal pain modulatory mechanism, termed conditioned pain modulation in humans. Microinjection of morphine into the BLA had no effects on evoked behaviors and did not produce CPP in nerve-injured rats. These findings demonstrate that the amygdalar action of morphine is specific to the right CeA contralateral to the side of injury and results in enhancement of net descending inhibition. In addition, engagement of mu opioid receptors in the right CeA modulates affective qualities of ongoing pain through endogenous opioid neurotransmission within the rACC, revealing opioid-dependent functional connections from the CeA to the rACC.
Tập 161 Số 3 - Trang 609-618 - 2020
Lateralized kappa opioid receptor signaling from the amygdala central nucleus promotes stress-induced functional pain Abstract
The response of diffuse noxious inhibitory controls (DNIC) is often decreased, or lost, in stress-related functional pain syndromes. Because the dynorphin/kappa opioid receptor (KOR) pathway is activated by stress, we determined its role in DNIC using a model of stress-induced functional pain. Male, Sprague-Dawley rats were primed for 7 days with systemic morphine resulting in opioid-induced hyperalgesia. Fourteen days after priming, when hyperalgesia was resolved, rats were exposed to environmental stress and DNIC was evaluated by measuring hind paw response threshold to noxious pressure (test stimulus) after capsaicin injection in the forepaw (conditioning stimulus). Morphine priming without stress did not alter DNIC. However, stress produced a loss of DNIC in morphine-primed rats in both hind paws that was abolished by systemic administration of the KOR antagonist, nor-binaltorphimine (nor-BNI). Microinjection of nor-BNI into the right, but not left, central nucleus of the amygdala (CeA) prevented the loss of DNIC in morphine-primed rats. Diffuse noxious inhibitory controls were not modulated by bilateral nor-BNI in the rostral ventromedial medulla. Stress increased dynorphin content in both the left and right CeA of primed rats, reaching significance only in the right CeA; no change was observed in the rostral ventromedial medulla or hypothalamus. Although morphine priming alone is not sufficient to influence DNIC, it establishes a state of latent sensitization that amplifies the consequences of stress. After priming, stress-induced dynorphin/KOR signaling from the right CeA inhibits DNIC in both hind paws, likely reflecting enhanced descending facilitation that masks descending inhibition. Kappa opioid receptor antagonists may provide a new therapeutic strategy for stress-related functional pain disorders.
Tập 159 Số 5 - Trang 919-928 - 2018
Kappa opioid signaling in the central nucleus of the amygdala promotes disinhibition and aversiveness of chronic neuropathic pain Abstract
Chronic pain is associated with neuroplastic changes in the amygdala that may promote hyper-responsiveness to mechanical and thermal stimuli (allodynia and hyperalgesia) and/or enhance emotional and affective consequences of pain. Stress promotes dynorphin-mediated signaling at the kappa opioid receptor (KOR) in the amygdala and mechanical hypersensitivity in rodent models of functional pain. Here, we tested the hypothesis that KOR circuits in the central nucleus of the amygdala (CeA) undergo neuroplasticity in chronic neuropathic pain resulting in increased sensory and affective pain responses. After spinal nerve ligation (SNL) injury in rats, pretreatment with a long-acting KOR antagonist, nor-binaltorphimine (nor-BNI), subcutaneously or through microinjection into the right CeA, prevented conditioned place preference (CPP) to intravenous gabapentin, suggesting that nor-BNI eliminated the aversiveness of ongoing pain. By contrast, systemic or intra-CeA administration of nor-BNI had no effect on tactile allodynia in SNL animals. Using whole-cell patch-clamp electrophysiology, we found that nor-BNI decreased synaptically evoked spiking of CeA neurons in brain slices from SNL but not sham rats. This effect was mediated through increased inhibitory postsynaptic currents, suggesting tonic disinhibition of CeA output neurons due to increased KOR activity as a possible mechanism promoting ongoing aversive aspects of neuropathic pain. Interestingly, this mechanism is not involved in SNL-induced mechanical allodynia. Kappa opioid receptor antagonists may therefore represent novel therapies for neuropathic pain by targeting aversive aspects of ongoing pain while preserving protective functions of acute pain.
Tập 160 Số 4 - Trang 824-832 - 2019
The stress regulator FKBP51: a novel and promising druggable target for the treatment of persistent pain states across sexes Abstract
It is well established that FKBP51 regulates the stress system by modulating the sensitivity of the glucocorticoid receptor to stress hormones. Recently, we have demonstrated that FKBP51 also drives long-term inflammatory pain states in male mice by modulating glucocorticoid signalling at spinal cord level. Here, we explored the potential of FKBP51 as a new pharmacological target for the treatment of persistent pain across the sexes. First, we demonstrated that FKBP51 regulates long-term pain states of different aetiologies independently of sex. Deletion of FKBP51 reduced the mechanical hypersensitivity seen in joint inflammatory and neuropathic pain states in female and male mice. Furthermore, FKBP51 deletion also reduced the hypersensitivity seen in a translational model of chemotherapy-induced pain. Interestingly, these 3 pain states were associated with changes in glucocorticoid signalling, as indicated by the increased expression, at spinal cord level, of the glucocorticoid receptor isoform associated with glucocorticoid resistance, GRβ , and increased levels of plasma corticosterone. These pain states were also accompanied by an upregulation of interleukin-6 in the spinal cord. Crucially, we were able to pharmacologically reduce the severity of the mechanical hypersensitivity seen in these 3 models of persistent pain with the unique FKBP51 ligand SAFit2. When SAFit2 was combined with a state-of-the-art vesicular phospholipid gel formulation for slow release, a single injection of SAFit2 offered pain relief for at least 7 days. We therefore propose the pharmacological blockade of FKBP51 as a new approach for the treatment of persistent pain across sexes, likely in humans as well as rodents.
Tập 159 Số 7 - Trang 1224-1234 - 2018
Angina pectoris during daily activities and exercise stress testing: The role of inducible myocardial ischemia and psychological distress
Tập 139 - Trang 551-561 - 2008
Effects of gustatory nerve transection and/or ovariectomy on oral capsaicin avoidance in rats
Tập 155 - Trang 814-820 - 2014