Plasma membrane poration by opioid neuropeptides: a possible mechanism of pathological signal transduction

Maximyuk, Oleksandr; Khmyz, V.; Lindskog, C-J; Vukojević, Vladana; Ivanova, T. A.; Bazov, Igor; Hauser, Kurt F.; Bakalkin, Georgy; Krishtal, O. A.

doi:10.1038/cddis.2015.39

Cited by 14 publications

(18 citation statements)

References 64 publications

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“…Additionally, non-receptor mediated actions could underlie Dyn A's neurotoxicity, as wt and mutant Dyn A have been shown to penetrate bilayer membranes in vitro (36,37). We speculate that R9C Dyn A may exert its relatively mild neurotoxicity via alternative routes such as inducing membrane leakage via membrane penetration leading to cellular dysfunction (14,36,38) contributing to the inconsistent responses under a specific pre-treatment. R9C Dyn A's relatively mild toxic effects may also be explained by its high oligomerisation properties.…”

Section: Discussionmentioning

confidence: 95%

Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23

et al. 2016

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Spinocerebellar ataxia type 23 (SCA23) is caused by missense mutations in prodynorphin, encoding the precursor protein for the opioid neuropeptides α-neoendorphin, Dynorphin (Dyn) A and Dyn B, leading to neurotoxic elevated mutant Dyn A levels. Dyn A acts on opioid receptors to reduce pain in the spinal cord, but its cerebellar function remains largely unknown. Increased concentration of or prolonged exposure to Dyn A is neurotoxic and these deleterious effects are very likely caused by an N-methyl-d-aspartate-mediated non-opioid mechanism as Dyn A peptides were shown to bind NMDA receptors and potentiate their glutamate-evoked currents. In the present study, we investigated the cellular mechanisms underlying SCA23-mutant Dyn A neurotoxicity. We show that SCA23 mutations in the Dyn A-coding region disrupted peptide secondary structure leading to a loss of the N-terminal α-helix associated with decreased κ-opioid receptor affinity. Additionally, the altered secondary structure led to increased peptide stability of R6W and R9C Dyn A, as these peptides showed marked degradation resistance, which coincided with decreased peptide solubility. Notably, L5S Dyn A displayed increased degradation and no aggregation. R6W and wt Dyn A peptides were most toxic to primary cerebellar neurons. For R6W Dyn A, this is likely because of a switch from opioid to NMDA- receptor signalling, while for wt Dyn A, this switch was not observed. We propose that the pathology of SCA23 results from converging mechanisms of loss of opioid-mediated neuroprotection and NMDA-mediated excitotoxicity.

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Section: Discussionmentioning

confidence: 95%

Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23

et al. 2016

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“…Activity of these left and right postural asymmetry inducing factors (PAFs) may be balanced in the symmetric brain, while CCI and UBI may impair the balance and shift an equilibrium in PAFs activity to favor the factors producing either the contralesional or ipsilesional hindlimb response. Some of the PAFs, for example, endogenous opioid peptides dynorphins and Met-enkephalin are involved in tissue injury, pain and stress, and overproduced after brain trauma and spinal cord injury (Hauser et al 2005 ; Hussain et al 2012 ; Maximyuk et al 2015 ; Smeets et al 2015 ). The overproduction or excessive release of these injury-associated PAFs may be similar after the left and right side CCI.…”

Section: Discussionmentioning

confidence: 99%

Unilateral traumatic brain injury of the left and right hemisphere produces the left hindlimb response in rats

et al. 2021

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Traumatic brain injury and stroke result in hemiplegia, hemiparesis, and asymmetry in posture. The effects are mostly contralateral; however, ipsilesional deficits may also develop. We here examined whether ablation brain injury and controlled cortical impact (CCI), a rat model of clinical focal traumatic brain injury, both centered over the left or right sensorimotor cortex, induced hindlimb postural asymmetry (HL-PA) with contralesional or ipsilesional limb flexion. The contralesional hindlimb was flexed after left or right side ablation injury. In contrast, both the left and right CCI unexpectedly produced HL-PA with flexion on left side. The flexion persisted after complete spinal cord transection suggesting that CCI triggered neuroplastic processes in lumbar neural circuits enabling asymmetric muscle contraction. Left limb flexion was exhibited under pentobarbital anesthesia. However, under ketamine anesthesia, the body of the left and right CCI rats bent laterally in the coronal plane to the ipsilesional side suggesting that the left and right injury engaged mirror-symmetrical motor pathways. Thus, the effects of the left and right CCI on HL-PA were not mirror-symmetrical in contrast to those of the ablation brain injury, and to the left and right CCI produced body bending. Ipsilateral effects of the left CCI on HL-PA may be mediated by a lateralized motor pathway that is not affected by the left ablation injury. Alternatively, the left-side-specific neurohormonal mechanism that signals from injured brain to spinal cord may be activated by both the left and right CCI but not by ablation injury.

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“…Importantly here, all the biological characteristics of chosen targets should be carefully analyzed, to ensure that the antiopioid action of a selected system, meant to be counteracted by a novel hybrid, actually results from activating the respective pain-promoting receptors(and not from other mechanisms). For example, bradykinin receptors, targeted by dynorphins, are proposed as an adjuvant target of opioid-derived hybrid compounds, but there is evidence that pathological effects of dynorphins observed in vivo result from their ability to form pores in cell membranes [ 165 ]. Relevant experimental validation, e.g., using specific receptor antagonists, should then precede the hybrid compound design and synthesis.…”

Section: Limitations and Challenges Of The Hybrid Drugs Approachmentioning

confidence: 99%

Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges

Starnowska-Sokół

Przewłocka

2020

Molecules

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When the first- and second-line therapeutics used to treat neuropathic pain (NP) fail to induce efficient analgesia—which is estimated to relate to more than half of the patients—opioid drugs are prescribed. Still, the pathological changes following the nerve tissue injury, i.a. pronociceptive neuropeptide systems activation, oppose the analgesic effects of opiates, enforcing the use of relatively high therapeutic doses in order to obtain satisfying pain relief. In parallel, the repeated use of opioid agonists is associated with burdensome adverse effects due to compensatory mechanisms that arise thereafter. Rational design of hybrid drugs, in which opioid ligands are combined with other pharmacophores that block the antiopioid action of pronociceptive systems, delivers the opportunity to ameliorate the NP-oriented opioid treatment via addressing neuropathological mechanisms shared both by NP and repeated exposition to opioids. Therewith, the new dually acting drugs, tailored for the specificity of NP, can gain in efficacy under nerve injury conditions and have an improved safety profile as compared to selective opioid agonists. The current review presents the latest ideas on opioid-comprising hybrid drugs designed to treat painful neuropathy, with focus on their biological action, as well as limitations and challenges related to this therapeutic approach.

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Plasma membrane poration by opioid neuropeptides: a possible mechanism of pathological signal transduction

Cited by 14 publications

References 64 publications

Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23

Altered secondary structure of Dynorphin A associates with loss of opioid signalling and NMDA-mediated excitotoxicity in SCA23

Unilateral traumatic brain injury of the left and right hemisphere produces the left hindlimb response in rats

Multifunctional Opioid-Derived Hybrids in Neuropathic Pain: Preclinical Evidence, Ideas and Challenges

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