Opioid hyperalgesia

BACKGROUND: The dorsal reticular nucleus is a pain facilitatory area involved in the diffuse noxious inhibitory controls (DNIC), through opioidergic mechanisms that are poorly understood. We hypothesized that signaling of µ-opioid receptors is altered in this area at prolonged chronic inflammatory pain and that this accounts for the loss of DNIC occurring in this condition. METHODS: Monoarthritis was induced in male Wistar rats (n=5-9/group) by tibiotarsal injection of complete Freund's adjuvant...

Chronic pain is a severely debilitating condition with enormous socioeconomic costs. Current treatment regimens with nonsteroidal anti-inflammatory drugs (NSAIDs), steroids, or opioids have been largely unsatisfactory with uncertain benefits or severe long-term side effects. This is mainly because chronic pain has a multifactorial aetiology. Although conventional pain medications can alleviate pain by keeping several dysfunctional pathways under control, they can mask other underlying pathological causes, ultimately worsening nerve pathologies and pain outcome...

INTRODUCTION: People who are dependent on opioids experience acute pain similar to other individuals. However, treating acute pain in these patients renders unique challenges such as opioid-induced hyperalgesia, opioid tolerance, withdrawal and stigma from healthcare providers. Thus, it is crucial to identify effective strategies for treating acute pain in this population and to highlight gaps in knowledge to create a high standard of care. The main objective of the proposed scoping review is to identify current strategies for treating the acute pain in individuals with opioid dependence or use disorder...

Remifentanil-induced hyperalgesia (RIH) is a common clinical phenomenon that limits the use of opioids in pain management. Esketamine, a non-competitive N -methyl-d-aspartate (NMDA) receptor antagonist, has been shown to prevent and treat RIH. However, the underlying effect mechanism of esketamine on RIH remains unclear. This study aimed to investigate the role and mechanism of esketamine in preventing and treating RIH based on the NMDA receptor-CaMKIIα pathway. In this study, an experimental animal model was used to determine the therapeutic effect of esketamine on pain elimination...

Remifentanil-induced hyperalgesia (RIH) represents a significant clinical challenge due to the widespread use of opioids in pain management. However, the molecular and cellular mechanisms underlying RIH remain elusive. This study aimed to unravel the role of spinal cord microglia, focusing on the Nrf2/HO-1 signaling pathway and TRPV4 channels in the development of RIH. We used both in vivo and in vitro models to investigate the activation state of spinal cord microglia, the expression of TRPV4 channels, and the modulation of the Nrf2/HO-1 pathway under remifentanil exposure...

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Background and Objectives : The effects of midazolam, a benzodiazepine, on pain perception are complex on both spinal and supraspinal levels. It is not yet known whether remimazolam clinically attenuates or worsens pain. The present study investigated the effect of intraoperative remimazolam on opioid-induced hyperalgesia (OIH) in patients undergoing general anesthesia. Materials and Methods : The patients were randomized into three groups: group RHR (6 mg/kg/h initial dose followed by 1 mg/kg/h remimazolam and 0...

Fibromyalgia (FM) is a chronic pain condition characterized by widespread musculoskeletal pain and other frequent symptoms such as fatigue, sleep disturbance, cognitive impairment, and mood disorder. Based on the view that intermittent stress would be the most probable etiology for FM, intermittent cold- and intermittent psychological stress-induced generalized pain (ICGP and IPGP) models in mice have been developed and validated as FM-like pain models in terms of the patho-physiological and pharmacotherapeutic features that are shared with clinical versions...

A new series of thiophenpiperazine amide derivatives as potent dual ligands for the μ-opioid (MOR) and sigma-1 (σ1 R) receptors are reported. Compound 23 exhibited good affinity to σ1 R (Ki  = 44.7 ± 7.05 nM) and high selectivity to σ2 R. Furthermore, Compound 23 exerted MOR agonism and σ1R antagonism and potent analgesic activity in animal moldes (the abdominal constriction test (ED50  = 3.83 mg/kg) and carrageenan-induced inflammatory hyperalgesia model (ED50  = 5...

Oxycodone is the most prescribed opioid for pain management and has been available in clinics for almost a century, but effects of chronic oxycodone have been studied less than morphine in preclinical and clinical studies. Newly developed depression has been coupled with chronic oxycodone use in a few clinical studies, but no preclinical studies have investigated the pathogenesis of oxycodone-induced depression. Gut microbiome changes following oxycodone use is an understudied area, and interleukin-17A (IL-17A) is linked to both the development of mood disorders and regulation of gut microbiome...

The mechanisms of β -caryophyllene (BCP)-induced analgesia are not well studied. Here, we tested the efficacy of BCP in an acute postsurgical pain model and evaluated its effect on the endocannabinoid system. Rats were treated with vehicle and 10, 25, 50, and 75 mg/kg BCP. Paw withdrawal responses to mechanical stimuli were evaluated using an electronic von Frey anesthesiometer. Endocannabinoids, including 2-arachidonoylglycerol (2-AG), were also evaluated in plasma and tissues using high-performance liquid chromatography-tandem mass spectrometry...

While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4...

While opioids remain amongst the most effective treatments for moderate-to-severe pain, their substantial side effect profile remains a major limitation to broader clinical use. One such side effect is opioid-induced hyperalgesia (OIH), which includes a transition from opioid-induced analgesia to pain enhancement. Evidence in rodents supports the suggestion that OIH may be produced by the action of opioids at Toll-like Receptor 4 (TLR4) either on immune cells that, in turn, produce pronociceptive mediators to act on nociceptors, or by a direct action at nociceptor TLR4...

We discuss the use of an inpatient multi-day continuous intravenous ketamine infusion for the treatment of opioid-induced hyperalgesia (OIH) and high fentanyl requirements in the case of a patient with a background of fibromyalgia/central sensitisation syndrome who underwent a complicated post-operative course following a right below-knee amputation for high-grade myxoid fibrosarcoma. The patient was successfully tapered off a total fentanyl patch dose of 162 mcg/hour every 72 hours (morphine equivalent dose of 389 mg/day) to short-acting hydromorphone 2 mg orally two times per day as needed (equivalent of 8 mg morphine sustained-release twice per day) during a 2-week admission with only mild withdrawal symptoms...

Repeated use of opioid analgesics may cause a paradoxically exacerbated pain known as opioid-induced hyperalgesia (OIH), which hinders effective clinical intervention for severe pain. Currently, little is known about the neural circuits underlying OIH modulation. Previous studies suggest that laterocapsular division of the central nucleus of amygdala (CeLC) is critically involved in the regulation of OIH. Our purpose is to clarify the role of the projections from infralimbic medial prefrontal cortex (IL) to CeLC in OIH...

We investigated the role that innate immunological signaling pathways, principally nod-like receptors (NLRs) and inflammasomes, in the manifestation of the contradictory outcomes associated with opioids, namely hyperalgesia, and tolerance. The utilization of opioids for pain management is prevalent; nonetheless, it frequently leads to an increased sensitivity to pain (hyperalgesia) and reduced efficacy of the medication (tolerance) over an extended period. This, therefore, represents a major challenge in the area of chronic pain treatment...

Opioids are powerful analgesic drugs that are used clinically to treat pain. However, chronic opioid use causes compensatory neuroadaptations that result in greater pain sensitivity during withdrawal, known as opioid withdrawal-induced hyperalgesia (OWIH). Cold nociception tests are commonly used in humans, but preclinical studies often use mechanical and heat stimuli to measure OWIH. Thus, further characterization of cold nociception stimuli is needed in preclinical models. We assessed three cold nociception tests-thermal gradient ring (5-30 °C, 5-50 °C, 15-40 °C, and 25-50 °C), dynamic cold plate (4 °C to -1 °C at -1 °C/min, -1 °C to 4 °C at +1 °C/min), and stable cold plate (10 °C, 6 °C, and 2 °C)-to measure hyperalgesia in a mouse protocol of heroin dependence...

Prolonged exposure to opioids causes an enhanced sensitivity to painful stimuli (opioid-induced hyperalgesia, OIH) and a need for increased opioid doses to maintain analgesia (opioid-induced tolerance, OIT), but the mechanisms underlying both processes remain obscure. We found that pharmacological block or genetic deletion of HCN2 ion channels in primary nociceptive neurons of male mice completely abolished OIH but had no effect on OIT. Conversely, pharmacological inhibition of central HCN channels alleviated OIT but had no effect on OIH...

About 25 million American adults experience pain daily and one of the most commonly prescribed drugs to treat pain are opioids. Prolonged opioid usage and dose escalations can cause a paradoxical response where patients experience enhanced pain sensitivity. This opioid induced hyperalgesia (OIH) is a major hurdle when treating pain in the clinic because its underlying mechanisms are still not fully understood. OIH is also commonly overlooked and lacks guidelines to prevent its onset. Research on pain disorders and opioid usage have recognized potential epigenetic drivers of disease including DNA methylation, histone modifications, miRNA regulation, but their involvement in OIH has not been well studied...

2,6-di- tert -butylphenol (2,6-DTBP) ameliorates mechanical allodynia and thermal hyperalgesia produced by partial sciatic nerve ligation in mice, and selectively inhibits HCN1 channel gating. We hypothesized that the clinically utilized non-anesthetic dimerized congener of 2,6-DTBP, probucol (2,6-di- tert -butyl-4-[2-(3,5-di- tert -butyl-4-hydroxyphenyl)sulfanylpropan-2-ylsulfanyl]phenol), would relieve the neuropathic phenotype that results from peripheral nerve damage, and that the anti-hyperalgesic efficacy in vivo would correlate with HCN1 channel inhibition in vitro...