Opioid receptors mRNAs expression and opioids agonist-dependent G-protein activation in the rat brain following neuropathy

Llorca-Torralba, Meritxell; Pilar-Cuéllar, Fuencisla; Borges, Gisela; Micó, J.A.; Berrocoso, Esther

doi:10.1016/j.pnpbp.2019.109857

Cited by 14 publications

(20 citation statements)

References 89 publications

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“…Studies in different experimental settings also yielded some contrasting results regarding regulation of opioid receptors in animal models of neuropathic pain. For example, in rat models, decreased mRNA levels of the DOP and KOP receptor were reported in the NAc at delayed time-points (1 month) but not at 1 week after nerve injury (Llorca-Torralba et al 2020 andChang et al 2014, respectively). However, these gene expression changes were not paralleled by analogous changes in agoniststimulated receptor activity (GTPγS binding), although the latter was altered in a manner apparently independent on the corresponding receptor transcript levels (Llorca-Torralba et al 2020).…”

Section: Discussionmentioning

confidence: 99%

“…For example, in rat models, decreased mRNA levels of the DOP and KOP receptor were reported in the NAc at delayed time-points (1 month) but not at 1 week after nerve injury (Llorca-Torralba et al 2020 andChang et al 2014, respectively). However, these gene expression changes were not paralleled by analogous changes in agoniststimulated receptor activity (GTPγS binding), although the latter was altered in a manner apparently independent on the corresponding receptor transcript levels (Llorca-Torralba et al 2020). On the other hand, consistent with our results, elevation of both KOP receptor mRNA and agonist-stimulated activity was demonstrated in the mouse at 14 days after peripheral nerve injury (Liu et al 2019).…”

Section: Discussionmentioning

confidence: 99%

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Neuropathic Pain Dysregulates Gene Expression of the Forebrain Opioid and Dopamine Systems

et al. 2020

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Disturbances in the function of the mesostriatal dopamine system may contribute to the development and maintenance of chronic pain, including its sensory and emotional/cognitive aspects. In the present study, we assessed the influence of chronic constriction injury (CCI) of the sciatic nerve on the expression of genes coding for dopamine and opioid receptors as well as opioid propeptides in the mouse mesostriatal system, particularly in the nucleus accumbens. We demonstrated bilateral increases in mRNA levels of the dopamine D1 and D2 receptors (the latter accompanied by elevated protein level), opioid propeptides proenkephalin and prodynorphin, as well as delta and kappa (but not mu) opioid receptors in the nucleus accumbens at 7 to 14 days after CCI. These results show that CCI-induced neuropathic pain is accompanied by a major transcriptional dysregulation of molecules involved in dopaminergic and opioidergic signaling in the striatum/nucleus accumbens. Possible functional consequences of these changes include opposite effects of upregulated enkephalin/delta opioid receptor signaling vs. dynorphin/ kappa opioid receptor signaling, with the former most likely having an analgesic effect and the latter exacerbating pain and contributing to pain-related negative emotional states.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Neuropathic Pain Dysregulates Gene Expression of the Forebrain Opioid and Dopamine Systems

et al. 2020

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“…The reported lack of a postsynaptic effect of KOP receptors on PB neuronal excitability (Christie and North, 1988), which we also observed here, further supports a faciliatory role for PB KOPs in nociceptive signaling. In a model of chronic pain, no changes were reported in KOP expression levels, despite significant increases in MOP expression (Llorca-Torralba et al, 2020). Whether there are changes in the strength of this pathway during chronic pain remain to be determined.…”

Section: Mop and Kop Have Mixed Effects On Pb Excitabilitymentioning

confidence: 96%

Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

Cramer

Silva-Cardoso

Keller

2020

Preprint

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The parabrachial nucleus (PB) is a hub for aversive behaviors, including those related to pain. We have shown that the expression of chronic pain is causally related to amplified activity of PB neurons, and to changes in synaptic inhibition of these neurons. These findings indicate that regulation of synaptic activity in PB may modulate pain perception and be involved in the pathophysiology of chronic pain. Here, we identify the roles in PB of signaling pathways that modulate synaptic functions. In pharmacologically isolated lateral PB neurons in acute mouse slices, we find that baclofen, a GABAB receptor agonist, suppresses the frequency of miniature inhibitory and excitatory postsynaptic currents (mIPSCs and mEPSC). Activation of μ-opioid peptide receptors with DAMGO had similar effects, while the κ-opioid peptide receptor agonist U-69593 suppressed mIPSC release but had no consistent effects on mEPSCs. Activation of cannabinoid type 1 receptors with WIN 55,212-2 reduced the frequency of both inhibitory and excitatory synaptic events, while the CB1 antagonist AM251 had opposite effects on mIPSC and mEPSC frequencies. AM251 increased the frequency of inhibitory events but led to a reduction in excitatory events through a GABAB mediated mechanism. Although none of the treatments produced a consistent effect on mIPSC or mEPSC amplitudes, baclofen and DAMGO both reliably activated a postsynaptic conductance. Together, these results demonstrate that signaling pathways known to modulate nociception, alter synaptic transmission and neuronal excitability in the lateral parabrachial nucleus and provide a basis for investigating the contributions of these systems to the development and maintenance of chronic pain.

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“…Neuropathic pain is associated with a reduction in MOR function in the brainstem, with decreased activation of G proteins likely due to increased phosphorylation of the receptor, leading to its desensitization [ 131 ]. Reduced MOR-mediated G-protein activity was shown in the PAG [ 132 ] and RVM [ 133 ] of neuropathic pain models. At the DRt, we recently showed that neuropathic pain leads to increased release of ENK peptides and desensitization of MOR [ 105 ].…”

Section: Opioidergic Modulation Of Brainstem Pain Control Circuitsmentioning

confidence: 99%

Monoaminergic and Opioidergic Modulation of Brainstem Circuits: New Insights Into the Clinical Challenges of Pain Treatment?

2021

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The treatment of neuropathic pain remains a clinical challenge. Analgesic drugs and antidepressants are frequently ineffective, and opioids may induce side effects, including hyperalgesia. Recent results on brainstem pain modulatory circuits may explain those clinical challenges. The dual action of noradrenergic (NA) modulation was demonstrated in animal models of neuropathic pain. Besides the well-established antinociception due to spinal effects, the NA system may induce pronociception by directly acting on brainstem pain modulatory circuits, namely, at the locus coeruleus (LC) and medullary dorsal reticular nucleus (DRt). The serotoninergic system also has a dual action depending on the targeted spinal receptor, with an exacerbated activity of the excitatory 5-hydroxytryptamine 3 (5-HT3) receptors in neuropathic pain models. Opioids are involved in the modulation of descending modulatory circuits. During neuropathic pain, the opioidergic modulation of brainstem pain control areas is altered, with the release of enhanced local opioids along with reduced expression and desensitization of μ-opioid receptors (MOR). In the DRt, the installation of neuropathic pain increases the levels of enkephalins (ENKs) and induces desensitization of MOR, which may enhance descending facilitation (DF) from the DRt and impact the efficacy of exogenous opioids. On the whole, the data discussed in this review indicate the high plasticity of brainstem pain control circuits involving monoaminergic and opioidergic control. The data from studies of these neurochemical systems in neuropathic models indicate the importance of designing drugs that target multiple neurochemical systems, namely, maximizing the antinociceptive effects of antidepressants that inhibit the reuptake of serotonin and noradrenaline and preventing desensitization and tolerance of MOR at the brainstem.

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Opioid receptors mRNAs expression and opioids agonist-dependent G-protein activation in the rat brain following neuropathy

Cited by 14 publications

References 89 publications

Neuropathic Pain Dysregulates Gene Expression of the Forebrain Opioid and Dopamine Systems

Neuropathic Pain Dysregulates Gene Expression of the Forebrain Opioid and Dopamine Systems

Control of synaptic transmission and neuronal excitability in the parabrachial nucleus

Monoaminergic and Opioidergic Modulation of Brainstem Circuits: New Insights Into the Clinical Challenges of Pain Treatment?

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