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Opioid hyperalgesia

Delia Aguado, Rocío Bustamante, Ignacio A Gómez de Segura
BACKGROUND: Drugs with antagonistic actions on the Toll-like receptor 4 (Tlr4), such as naloxone at ultra low doses, have been used to inhibit opioid-induced hyperalgesia in rodents suggesting the involvement of this receptor and pathway on opioid-induced hyperalgesia. OBJECTIVE: The aim of this study was to determine whether mice without the Tlr4 gene (Tlr4) would not develop remifentanil-induced hyperalgesia. DESIGN: An experimental randomised animal study...
March 13, 2018: European Journal of Anaesthesiology
Jenny L Wilkerson, Zachary A Curry, Pamela D Kinlow, Brittany L Mason, Ku-Lung Hsu, Mario van der Stelt, Benjamin F Cravatt, Aron H Lichtman
A great need exists for the identification of new effective analgesics to treat sustained pain. However, most preclinical nociceptive assays measure behavioral responses evoked by noxious stimuli (i.e., pain-stimulated behavior), which presents a challenge to distinguish between motor impairing and antinociceptive effects of drugs. Here, we demonstrate that chronic constriction injury of the sciatic nerve (CCI) elicits common pain-stimulated responses (i.e., mechanical allodynia and thermal hyperalgesia) as well as reduces marble burying/digging behaviors that occur during the early stages of the neuropathy and resolve within one week...
March 8, 2018: Pain
Peter Athanasos, Walter Ling, Felix Bochner, Jason M White, Andrew A Somogyi
Objective: Acute pain management in opioid-dependent persons is complicated because of tolerance and opioid-induced hyperalgesia. Very high doses of morphine are ineffective in overcoming opioid-induced hyperalgesia and providing antinociception to methadone-maintained patients in an experimental setting. Whether the same occurs in buprenorphine-maintained subjects is unknown. Design: Randomized double-blind placebo-controlled. Subjects were tested on two occasions, at least five days apart, once with intravenous morphine and once with intravenous saline...
March 5, 2018: Pain Medicine: the Official Journal of the American Academy of Pain Medicine
Xinran Hou, Yingqi Weng, Tongxuan Wang, Bihan Ouyang, Yalin Li, Zongbin Song, Yundan Pan, Zhong Zhang, Wangyuan Zou, Changsheng Huang, Qulian Guo
Epigenetic modulation participates in the mechanism of multiple types of pathological pain, so targeting the involved regulators may be a promising strategy for pain treatment. Our previous research identified the analgesic effect of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on mechanical hyperalgesia in a rat model of bone cancer pain (BCP) via restoration of μ-opioid receptor (MOR) expression. However, the specific types of HDACs contributing to BCP have not been explored. The present study investigated the expression pattern of some common HDACs and found that HDAC2 was up-regulated in a time-dependent manner in the lumbar spinal cord of BCP rats...
February 23, 2018: Neuroscience
Rafael Salas, Karla Ramirez, Victor Tortorici, Horacio Vanegas, Enrique Vazquez
The so-called on- and off-cells of the rostral ventromedial medulla (RVM) send their axons to the spinal dorsal horn. Activation of on-cells precedes and coincides with a facilitation, and activation of off-cells coincides with an inhibition, of withdrawal reflexes elicited by noxious agents. Considerable evidence supports the notion that on- and off-cells modulate nocifensive reflexes during opioid and non-opioid action and also during normal circumstances and during peripheral neuropathy and inflammation...
February 21, 2018: Brain Research
Kornél Király, Márk Kozsurek, Erika Lukácsi, Benjamin Barta, Alán Alpár, Tamás Balázsa, Csaba Fekete, Judit Szabon, Zsuzsanna Helyes, Kata Bölcskei, Valéria Tékus, Zsuzsanna E Tóth, Károly Pap, Gábor Gerber, Zita Puskár
Altered pain sensations such as hyperalgesia and allodynia are characteristic features of various pain states, and remain difficult to treat. We have shown previously that spinal application of dipeptidyl peptidase 4 (DPP4) inhibitors induces strong antihyperalgesic effect during inflammatory pain. In this study we observed low level of DPP4 mRNA in the rat spinal dorsal horn in physiological conditions, which did not change significantly either in carrageenan-induced inflammatory or partial nerve ligation-generated neuropathic states...
February 22, 2018: Scientific Reports
Yusuke Ohmichi, Mika Ohmichi, Nobuhito Murai, Masaya Yasui, Nobuaki Takeshita, Hidehiro Oshibuchi, Munekazu Naito, Takashi Nakano, Jun Sato
The aim of this study was to clarify the mechanism of disuse-induced muscle hyperalgesia through the evaluation of the pharmacological behaviour of muscle hyperalgesia profiles in chronic post-cast pain (CPCP) rats with acute and chronic-phase mirror-image muscle hyperalgesia treated with diclofenac (NSAID), pregabalin (an inhibitor of Ca2+ channel α2δ), and duloxetine (SNRI). After 2 weeks of cast immobilization, the peak cross-sectional area and muscle wet weight of the ipsilateral soleus and gastrocnemius muscles decreased more significantly in CPCP rats than in untreated rats...
February 19, 2018: Scientific Reports
Dionéia Araldi, Luiz F Ferrari, Jon D Levine
Repeated stimulation of mu-opioid receptors (MORs), by an MOR-selective agonist DAMGO induces type II priming, a form of nociceptor neuroplasticity, which has 2 components: opioid-induced hyperalgesia (OIH) and prolongation of prostaglandin-E2 (PGE2)-induced hyperalgesia. We report that intrathecal antisense knockdown of the MOR in nociceptors, prevented the induction of both components of type II priming. Type II priming was also eliminated by SSP-saporin, which destroys the peptidergic class of nociceptors...
January 11, 2018: Pain
Lusha Xiang, Harold G Klemcke, Nathan A Wienandt, Kathy L Ryan, Carmen Hinojosa-Laborde
BACKGROUND: Pain management is important in pre-hospital care of patients with extremity trauma (ET). The goal of this study was to establish a rat model of ET for pre-hospital pain research, and validate it using pain behaviors and analgesics. METHODS: Rats were anesthetized using isoflurane and ET was induced in one hindlimb via clamping retrofemoral tissues for 30 sec, followed by closed fibula fracture. Rats regained consciousness after ET. Pain responses in the injured hindlimb to thermal hyperalgesia (paw withdrawal latency, PWL), mechanical allodynia (paw withdrawal pressure, PWP), and weight bearing (WB) were determined before and 90 minutes after ET...
February 14, 2018: Journal of Trauma and Acute Care Surgery
Aifen Liu, Xiaopeng Wang, Hui Wang, Guoyi Lv, Yize Li, Hongmei Li
The interaction of remifentanil with glutamate systems has an important role in remifentanil-induced thermal and mechanical hyperalgesia. A previous study by our group suggested that the trafficking and function of glutamate receptor 1 (GluR1) subunits contributes to remifentanil-induced hyperalgesia by regulating the phosphorylation of GluR1 in dorsal horn neurons. The present study demonstrated that δ opioid receptor (DOR) inhibition prevented thermal and mechanical hyperalgesia, which was induced by remifentanil infusion via attenuating GluR1 subunit trafficking and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function in dorsal horn neurons...
February 2018: Experimental and Therapeutic Medicine
Dioneia Araldi, Eugen V Khomula, Luiz F Ferrari, Jon D Levine
Systemic fentanyl induces hyperalgesic priming, long-lasting neuroplasticity in nociceptor function characterized by prolongation of inflammatory mediator hyperalgesia. To evaluate priming at both nociceptor terminals, we studied, in male Sprague--Dawley rats, the effect of local administration of agents that reverse Type I (protein translation) or Type II (combination of Src and mitogen-activated protein kinase [MAPK]) priming. While at the central terminal, priming induced by systemic, intradermal or intrathecal fentanyl was reversed by the combination of Src and MAPK inhibitors, at the peripheral terminal it was reversed by the protein translation inhibitor...
February 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Viljami Jokinen, Yulia Sidorova, Hanna Viisanen, Ilida Suleymanova, Henna Tiilikainen, Zhilin Li, Tuomas O Lilius, Kert Mätlik, Jenni E Anttila, Mikko Airavaara, Li Tian, Pekka V Rauhala, Eija A Kalso
Development of tolerance is a well known pharmacological characteristic of opioids and a major clinical problem. In addition to the known neuronal mechanisms of opioid tolerance, activation of glia has emerged as a potentially significant new mechanism. We studied activation of microglia and astrocytes in morphine tolerance and opioid-induced hyperalgesia in rats using immunohistochemistry, flow cytometry and RNA sequencing in spinal- and supraspinal regions. Chronic morphine treatment that induced tolerance and hyperalgesia also increased immunoreactivity of spinal microglia in the dorsal and ventral horns...
February 6, 2018: Neuroscience
Vinita Singh, Theresa W Gillespie, R Donald Harvey
Cancer-related pain continues to be a significant therapeutic challenge, made more difficult by contemporary opioid use and diversion concerns. Conventional treatment utilizing a tiered approach of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and adjuvant agents is limited; and alternatives are needed for patients with rapidly progressing pain and those who develop hyperalgesia and tolerance to opioids. Ketamine, an N-methyl-D-aspartate (NMDA) selective antagonist, has historically been used for anesthesia in adult and pediatric populations, but has also been investigated for depression, bipolar disorder, and general and post-operative pain management...
February 3, 2018: Pharmacotherapy
Renan G Brito, Lynn A Rasmussen, Kathleen A Sluka
Introduction: It is generally believed that exercise produces its effects by activating central opioid receptors; there are little data that support this claim. The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are key nuclei in opioid-induced analgesia, and opioids interact with serotonin to produce analgesia. Objectives: The purpose was to examine central inhibitory mechanisms involved in analgesia produced by wheel running. Methods: C57/Black6 mice were given access to running wheels in their home cages before induction of chronic muscle hyperalgesia and compared with those without running wheels...
September 2017: Pain Reports (Baltimore, Md.)
Esther M Pogatzki-Zahn, Daniel Segelcke, Stephan A Schug
Introduction: Pain management after surgery continues to be suboptimal; there are several reasons including lack of translation of results from basic science studies and scientific clinical evidence into clinical praxis. Objectives: This review presents and discusses basic science findings and scientific evidence generated within the last 2 decades in the field of acute postoperative pain. Methods: In the first part of the review, we give an overview about studies that have investigated the pathophysiology of postoperative pain by using rodent models of incisional pain up to July 2016...
March 2017: Pain Reports (Baltimore, Md.)
Kelsey M Nation, Milena De Felice, Pablo I Hernandez, David W Dodick, Volker Neugebauer, Edita Navratilova, Frank Porreca
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)...
January 23, 2018: Pain
Aizhu Lu, Lei Hongyi, Le Li, Luying Lai, Wenbin Liang, Shiyuan Xu
Opioid-induced hyperalgesia and allodynia (OIH) is a well-known phenomenon and refers to the pain sensitization in patients after prolonged opioid exposure. OIH limits the use of opioids in pain control, but the underlying mechanisms are not fully clear. The present study investigated the role of mitochondrial Ca2+ uniporter (MCU) in remifentanil (a commonly used opioid analgesic)-induced allodynia. Using a rat model of OIH, we found that incision- and remifentanil-induced mechanical allodynia were remarkably attenuated by pretreatment with Ru360, a specific MCU antagonist, suggesting a critical role of MCU in both incision- and opioid-induced allodynia...
January 24, 2018: European Journal of Neuroscience
F Resta, L Micheli, A Laurino, V Spinelli, T Mello, L Sartiani, L Di Cesare Mannelli, E Cerbai, C Ghelardini, M N Romanelli, G Mannaioni, A Masi
Chemotherapy-Induced Peripheral Neuropathy (CIPN) is the most frequent adverse effect of pharmacological cancer treatments. The occurrence of neuropathy prevents the administration of fully-effective drug regimen, affects negatively the quality of life of patients, and may lead to therapy discontinuation. CIPN is currently treated with anticonvulsants, antidepressants, opioids and non-opioid analgesics, all of which are flawed by insufficient anti-hyperalgesic efficacy or addictive potential. Understandably, developing new drugs targeting CIPN-specific pathogenic mechanisms would dramatically improve efficacy and tolerability of anti-neuropathic therapies...
January 12, 2018: Neuropharmacology
Amanda H Klein, Husam K Mohammad, Rabiah Ali, Brad Peper, Steven P Wilson, Srinivasa N Raja, Matthias Ringkamp, Sarah Sweitzer
BACKGROUND: The current study used recombinant herpes simplex virus type I to increase expression of µ-opiate receptors and the opioid ligand preproenkephalin in peripheral nerve fibers in a mouse model of neuropathic pain. It was predicted that viral vector delivery of a combination of genes encoding the µ-opioid receptor and preproenkephalin would attenuate neuropathic pain and enhance opioid analgesia. The behavioral effects would be paralleled by changes in response properties of primary afferent neurons...
January 15, 2018: Anesthesiology
Fei Li, LiPing Liu, Kathleen Cheng, Zhongbo Chen, Jianguo Cheng
Opioid tolerance (OT) and opioid-induced hyperalgesia (OIH) are major challenges in medicine. Here we report that transplantation of mesenchymal stem cells (MSCs) prevented and reversed OT and OIH in rats and mice. The preventive and therapeutic effects were long-lasting and consistent across different assessment schemes. Both intrathecal and intravenous transplantations were effective and safe. This emerging therapeutic strategy has thus shown promise to impact clinical practice and improve the efficacy and safety of opioid therapy...
December 29, 2017: Clinical Pharmacology and Therapeutics
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