Role of Neuroinflammation in Opioid Tolerance: Translational Evidence from Human-to-Rodent Studies

Lin, Chih-Peng; Lu, Dai‐Hua

doi:10.1007/978-981-13-1756-9_11

Cited by 19 publications

(7 citation statements)

References 60 publications

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“…Multiple mechanisms have been shown to mediate opioid analgesic tolerance, OIH, and addiction implicating neuroinflammation, and, in particular, microglial activation (Cahill & Taylor, 2017;Eidson & Murphy, 2019;Rivat & Ballantyne, 2016;Roeckel, Coz, Gaveriaux-Ruff, & Simonin, 2016). Opioid-induced neuroimmune reactions dysregulate physiological reward and analgesia processes, thus contributing to tolerance, withdrawal, and addiction (Cahill & Taylor, 2017;Chen, Zhang, Qadri, Serhan, & Ji, 2018;Eidson & Murphy, 2019;Lin & Lu, 2018;Melik Parsadaniantz, Rivat, Rostene, & Reaux-Le Goazigo, 2015). Experimental evidence using whole-body knockout (KO) mice and pharmacological interventions indicates that MOR, encoded by Oprm1 gene, is critical for both opiate analgesia, and side effects including analgesic tolerance, physical dependence (Maldonado, Banos, & Cabanero, 2018), and OIH (Corder et al, 2017;Roeckel et al, 2017).…”

Section: Introductionmentioning

confidence: 99%

Mu opioid receptor in microglia contributes to morphine analgesic tolerance, hyperalgesia, and withdrawal in mice

Reiss

Maduna

Maurin

et al. 2020

J of Neuroscience Research

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A major challenge in medicine is developing potent pain therapies without the adverse effects of opiates. Neuroinflammation and in particular microglial activation have been shown to contribute to these effects. However, the implication of the microglial mu opioid receptor (MOR) is not known. We developed a novel conditional knockout (cKO) mouse line, wherein MOR is deleted in microglia. Morphine analgesic tolerance was delayed in both sexes in cKO mice in the hot plate assay. Opioid-induced hyperalgesia (OIH) as measured in the tail immersion assay was abolished in male cKO mice, and physical dependence to morphine as assessed by naloxone-induced withdrawal was attenuated in female cKO mice. Our results show a sex-dependent contribution of microglial MOR in morphine analgesic tolerance, OIH, and physical dependence.In conclusion, our data suggest that blockade of microglial MOR could represent a therapeutic target for opiate analgesia without the opiate adverse effects.

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Section: Introductionmentioning

confidence: 99%

Mu opioid receptor in microglia contributes to morphine analgesic tolerance, hyperalgesia, and withdrawal in mice

Reiss

Maduna

Maurin

et al. 2020

J of Neuroscience Research

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“…This approach resulted in significantly reduced antinociceptive tolerance and spinal microglial activation [ 208 , 209 ]. Moreover, the expression of other chemokines and their receptors, such as CXCL1/CXCR2, CXCL10/CXCR3, and CXCR12/CXCR4, is increased by opioids and seems to be associated with analgesic tolerance [ 210 , 211 , 212 , 213 ].…”

Section: Chemokine System As Novel Target For Enhancing Opioid Analge...mentioning

confidence: 99%

Targeting Chemokines and Chemokine GPCRs to Enhance Strong Opioid Efficacy in Neuropathic Pain

Vincenzi

Milella

D’Ottavio

et al. 2022

Life

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Neuropathic pain (NP) originates from an injury or disease of the somatosensory nervous system. This heterogeneous origin and the possible association with other pathologies make the management of NP a real challenge. To date, there are no satisfactory treatments for this type of chronic pain. Even strong opioids, the gold-standard analgesics for nociceptive and cancer pain, display low efficacy and the paradoxical ability to exacerbate pain sensitivity in NP patients. Mounting evidence suggests that chemokine upregulation may be a common mechanism driving NP pathophysiology and chronic opioid use-related consequences (analgesic tolerance and hyperalgesia). Here, we first review preclinical studies on the role of chemokines and chemokine receptors in the development and maintenance of NP. Second, we examine the change in chemokine expression following chronic opioid use and the crosstalk between chemokine and opioid receptors. Then, we examine the effects of inhibiting specific chemokines or chemokine receptors as a strategy to increase opioid efficacy in NP. We conclude that strong opioids, along with drugs that block specific chemokine/chemokine receptor axis, might be the right compromise for a favorable risk/benefit ratio in NP management.

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“…It has been well documented that chronic morphine exposure-induced spinal neuroinflammation plays critical role in the development and maintenance of morphine analgesic tolerance and hyperalgesia [16,17]. Therefore, we promised that as pro-inflammatory cytokines and chemokines, spinal HMGB1 might be another important morphine-induced inflammatory mediator and contribute to the development of morphine tolerance.…”

Section: Introductionmentioning

confidence: 96%

Chronic morphine-mediated upregulation of high mobility group box 1 in the spinal cord contributes to analgesic tolerance and hyperalgesia in rats

et al. 2020

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Analgesic tolerance and hyperalgesia hinder the long-term utility of opioids. We examined whether spinal high mobility group box 1 (HMGB1) is involved in morphine tolerance and its underlying mechanisms by using a model of repeated intrathecal (i.t.) injections of morphine. The results showed that chronic i.t. morphine exposure led to increased expression of HMGB1, Toll-like receptor 4 (TLR4), and receptor for advanced glycation end products (RAGE) and their mRNAs in the dorsal horn. Morphine challenge also promoted HMGB1 expression and release in cultured spinal neurons, but these effects were inhibited by TAK-242, naloxone (antagonists of TLR4), and TLR4 siRNA. Intrathecal coadministration of morphine with TAK-242 or PDTC (inhibitor of NF-κB activation) also reduced HMGB1 expression in the spinal cord. Repeated i.t. coinjections of morphine with glycyrrhizin (GL, an HMGB1 inhibitor) or HMGB1 siRNA prevented reduction of the maximal possible analgesic effect (MPAE) of morphine and alleviated morphine withdrawal-induced hyperalgesia. The established morphine tolerance and hyperalgesia were partially reversed when i.t. injections of GL or HMGB1 antibody started at day 7 of morphine injection. Repeated i.t. injections of morphine with HMGB1 siRNA inhibited the activation of NF-κB, but not that of JNK and p38. A single i.t. injection of HMGB1 in naïve rats caused pain-related hypersensitivity and reduction in MPAE. Moreover, phosphorylated NF-κB p65, TNF-α, and IL-1β levels in the dorsal horn were upregulated following this treatment, but this upregulation was prevented by coinjection with TAK-242. Together, these results suggest that morphine-mediated upregulation of spinal HMGB1 contributes to analgesic tolerance and hyperalgesia via activation of TLR4/NF-κB signaling, and the HMGB1 inhibitor might be a promising adjuvant to morphine in the treatment of intractable pain in the clinic.

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Role of Neuroinflammation in Opioid Tolerance: Translational Evidence from Human-to-Rodent Studies

Cited by 19 publications

References 60 publications

Mu opioid receptor in microglia contributes to morphine analgesic tolerance, hyperalgesia, and withdrawal in mice

Mu opioid receptor in microglia contributes to morphine analgesic tolerance, hyperalgesia, and withdrawal in mice

Targeting Chemokines and Chemokine GPCRs to Enhance Strong Opioid Efficacy in Neuropathic Pain

Chronic morphine-mediated upregulation of high mobility group box 1 in the spinal cord contributes to analgesic tolerance and hyperalgesia in rats

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