Blockade of kappa opioid receptors reduces mechanical hyperalgesia and anxiety-like behavior in a rat model of trigeminal neuropathic pain

Turnes, Joelle de Melo; Araya, Erika Ivanna; Barroso, Amanda Ribeiro; Baggio, Darciane Favero; Koren, Laura de Oliveira; Zanoveli, Janaína Menezes; Chichorro, Juliana Geremias

doi:10.1016/j.bbr.2021.113595

Cited by 16 publications

(4 citation statements)

References 71 publications

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“…This is consistent with prior studies showing that a KOR antagonist (nor-BNI) in the right CeA decreased CRF output signaling and emotional responses, anxiety-like behaviors, and hypersensitivity in a functional pain model [27] and relieved aversiveness, but not hypersensitivity, in a neuropathic pain model [26]. nor-BNI administered into the right (but not left) CeA prevented mechanical hypersensitivity in an injury-free model of functional cephalic pain [48], decreased facial mechanical hyperalgesia, but not anxiety-like behavior, in a model of trigeminal neuropathic pain [54], and restored descending pain modulation (diffuse noxious inhibitory control) that was impaired by stress [31] or neuropathic pain [32,55]. These results are consistent with evidence for increased dynorphin or dynorphin signaling in the amygdala in certain pain conditions [56,57].…”

Section: Discussionmentioning

confidence: 99%

Chemogenetic Manipulation of Amygdala Kappa Opioid Receptor Neurons Modulates Amygdala Neuronal Activity and Neuropathic Pain Behaviors

Ji,

Presto,

Kiritoshi

et al. 2024

Cells

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Neuroplasticity in the central nucleus of the amygdala (CeA) plays a key role in the modulation of pain and its aversive component. The dynorphin/kappa opioid receptor (KOR) system in the amygdala is critical for averse-affective behaviors in pain conditions, but its mechanisms are not well understood. Here, we used chemogenetic manipulations of amygdala KOR-expressing neurons to analyze the behavioral consequences in a chronic neuropathic pain model. For the chemogenetic inhibition or activation of KOR neurons in the CeA, a Cre-inducible viral vector encoding Gi-DREADD (hM4Di) or Gq-DREADD (hM3Dq) was injected stereotaxically into the right CeA of transgenic KOR-Cre mice. The chemogenetic inhibition of KOR neurons expressing hM4Di with a selective DREADD actuator (deschloroclozapine, DCZ) in sham control mice significantly decreased inhibitory transmission, resulting in a shift of inhibition/excitation balance to promote excitation and induced pain behaviors. The chemogenetic activation of KOR neurons expressing hM3Dq with DCZ in neuropathic mice significantly increased inhibitory transmission, decreased excitability, and decreased neuropathic pain behaviors. These data suggest that amygdala KOR neurons modulate pain behaviors by exerting an inhibitory tone on downstream CeA neurons. Therefore, activation of these interneurons or blockade of inhibitory KOR signaling in these neurons could restore control of amygdala output and mitigate pain.

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Section: Discussionmentioning

confidence: 99%

Chemogenetic Manipulation of Amygdala Kappa Opioid Receptor Neurons Modulates Amygdala Neuronal Activity and Neuropathic Pain Behaviors

Ji,

Presto,

Kiritoshi

et al. 2024

Cells

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“…49 Moreover, blockade of κ-opioid receptor reduces mechanical hyperalgesia and anxiety-like behavior in a rat model of trigeminal neuropathic allodynia–like behavior. 50 Thus, other opioid receptors for UPF1-dependent nonsense-mediated mRNA decay in neuropathic allodynia–like behaviors in rats need to be investigated further.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated Upstream Frameshift 1–dependent Nonsense-mediated μ-Opioid Receptor mRNA Decay in the Spinal Cord Contributes to the Development of Neuropathic Allodynia–like Behavior in Rats

et al. 2023

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Background Nonsense-mediated mRNA decay increases targeted mRNA degradation and has been implicated in the regulation of gene expression in neurons. We hypothesized that nonsense-mediated μ opioid receptor mRNA decay in the spinal cord is involved in the development of neuropathic allodynia-like behavior in rats. Methods Adult Sprague-Dawley rats of both sexes received spinal nerve ligation to induce neuropathic allodynia-like behavior. The mRNA and protein expression contents in the dorsal horn of animals were measured by biochemical analyses. Nociceptive behaviors were evaluated by the von Frey test and the burrow test. Results On Day 7, spinal nerve ligation significantly increased phosphorylated upstream frameshift 1 (pUPF1) expression in the dorsal horn (0.34 ± 0.19 in the sham ipsilateral group versus 0.88 ± 0.15 in the nerve ligation ipsilateral group, p < 0.001, data in arbitrary units) and drove allodynia-like behaviors in rats (10.58 ± 1.72 g in the sham ipsilateral group versus 1.19 ± 0.31 g in the nerve ligation ipsilateral group, p < 0.001). No sex-based differences were found in either Western blotting or behavior tests in rats. Eukaryotic translation initiation factor 4A3 triggered SMG1 kinase (0.06 ± 0.02 in the sham group versus 0.20 ± 0.08 in the nerve ligation group, p = 0.005, data in arbitrary units)-mediated UPF1 phosphorylation, leading to increased nonsense-mediated mRNA decay factor SMG7 binding and µ-opioid receptor mRNA degradation (0.87 ± 0.11 fold in the sham group versus 0.50 ± 0.11 fold in the nerve ligation group, p = 0.002) in the dorsal horn of the spinal cord after spinal nerve ligation. Pharmacological or genetic inhibition of this signaling pathway in vivo ameliorated allodynia-like behaviors following spinal nerve ligation. Conclusions Our study suggests that phosphorylated upstream frameshift 1-dependent nonsense-mediated μ opioid receptor mRNA decay is involved in the pathogenesis of neuropathic pain.

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“…α -adrenergic receptors might be other analgesic pathways of pentazocine as phentolamine alone is effective in reducing pentazocine's analgesic effects [ 28 ]. Nor-BNI is a highly selective kappa-opioid receptor antagonist that can partially antagonize the action of morphine and fentanyl [ 29 ]. In our results, the synergistic effects between pentazocine and neostigmine can be antagonized by the nonselective opioid receptor antagonist naloxone and the κ -opioid receptor antagonist nor-BNI, but not antagonized by the µ -opioid receptor antagonist CTAP.…”

Section: Discussionmentioning

confidence: 99%

Antinociceptive Effects and Interaction Mechanisms of Intrathecal Pentazocine and Neostigmine in Two Different Pain Models in Rats

Huang

Xiu-juan

Zhang

et al. 2022

Pain Research and Management

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Background. Pentazocine produces a wide variety of actions in the treatment of perioperative analgesia. Neostigmine is a cholinesterase inhibitor used to antagonize the residual effects of muscle relaxants and also produces an analgesic effect. Objectives. To investigate the analgesic effects of intrathecally injected pentazocine and neostigmine and their interaction. Methods. Sprague–Dawley rats were used to test the analgesic effect of pentazocine and neostigmine using the paw formalin pain model and the incision mechanical allodynia model. Pentazocine (3, 10, 30, and 100 μg), neostigmine (0.3, 1, 3, and 10 μg) or a pentazocine-neostigmine mixture were separately injected to evaluate their antinociceptive effects alone on the treatment groups. The corresponding control group received an intrathecal injection containing the same volume of saline. The formalin pain test, or the plantar incision pain behavior test were performed 30 minutes later. Isobolographic analysis was used to evaluate the interaction between pentazocine and neostigmine. Intrathecally administered selective mu-opioid receptor antagonist CTAP, selective kappa-opioid receptor antagonist nor-Binaltorphimine (nor-BNI), nonselective opioid receptor antagonist naloxone, and muscarinic acetylcholine receptor antagonist atropine were also used to test the possible interaction mechanism. These antagonists were used 30 minutes before the pentazocine and neostigmine mixtures which were intrathecally injected. Results. Intrathecally administered pentazocine (3, 10, 30, and 100 μg) and neostigmine (0.3, 1, 3, and 10 μg) alone had a marked dose-related impact on suppressing the biphasic responses in the formalin test. Pentazocine (3, 10, 30, and 100 μg) and neostigmine (0.3, 1, 3, and 10 μg) alone attenuated the mechanical allodynia in a plantar incision model in a dose-dependent manner. Isobolographic analysis revealed that the mixture of intrathecal pentazocine and neostigmine synergistically decreased both phase I and II activity in the formalin test and mechanical allodynia in the plantar incision model. Pretreatment of intrathecally administered nor-BNI, naloxone, atropine, but not CTAP, antagonized the analgesic effect of the pentazocine-neostigmine mixture. Conclusions. All of these results suggest that the combined application of pentazocine and neostigmine is an effective way to relieve pain from formalin and acute incision mechanical allodynia. The synergistic effect between pentazocine and neostigmine is mostly attributed to the kappa-opioid receptor and the cholinergic receptor in the spinal cord.

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Blockade of kappa opioid receptors reduces mechanical hyperalgesia and anxiety-like behavior in a rat model of trigeminal neuropathic pain

Cited by 16 publications

References 71 publications

Chemogenetic Manipulation of Amygdala Kappa Opioid Receptor Neurons Modulates Amygdala Neuronal Activity and Neuropathic Pain Behaviors

Chemogenetic Manipulation of Amygdala Kappa Opioid Receptor Neurons Modulates Amygdala Neuronal Activity and Neuropathic Pain Behaviors

Phosphorylated Upstream Frameshift 1–dependent Nonsense-mediated μ-Opioid Receptor mRNA Decay in the Spinal Cord Contributes to the Development of Neuropathic Allodynia–like Behavior in Rats

Antinociceptive Effects and Interaction Mechanisms of Intrathecal Pentazocine and Neostigmine in Two Different Pain Models in Rats

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