Sex differences in kappa opioid receptor inhibition of latent postoperative pain sensitization in dorsal horn

Custodio-Patsey, Lilian; Donahue, Renée R.; Fu, Weisi; Lambert, Joshua; Smith, Bret N.; Taylor, Bradley K.

doi:10.1016/j.neuropharm.2019.107726

Cited by 25 publications

(28 citation statements)

References 79 publications

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“…On the other hand, it may be a confound in animal studies where JNJ-67953964 is centrally administered e.g. [43]. In our selectivity experiments, we also saw modest blockade of our DAMGO induced effects at just 10 nM JNJ-67953964.…”

Section: Discussionmentioning

confidence: 49%

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

Margolis

Wallace

Orden

et al. 2020

Preprint

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19Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of 20 stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR 21 agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to 22 aversive responses [1,2]; therefore, selective KOR antagonists represent a novel therapeutic 23 approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain 24 slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, 25 BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently 26 reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and 27 BTRX-395750 fully blocked U-69,593 currents (IC 50 = 1.3 ± 0.9 and 4.6 ± 0.9 nM, respectively).28 JNJ-67953964 showed an IC 50 of 0.3 ± 1.3 nM. PF-04455242 (IC 50 = 19.6 ± 16 nM) exhibited 29 partial antagonist activity (~60% maximal blockade). In 50% of neurons, 1 M PF-04455242 30 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not 31 affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO 32 or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked 33 DAMGO responses and had no effect on DPDPE responses. Importantly, BTRX-335140 (10 nM) 34 rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we 35 show electrophysiological evidence of key differences amongst KOR antagonists that could 36 impact their therapeutic potential and have not been observed using recombinant systems. The 37 results of this study demonstrate the value of characterizing compounds in native neuronal tissue 38 and within disorder-relevant circuits implicated in neurobehavioral disorders. Introduction 40One of the major challenges in drug development is predicting whole animal responses 42 indicate that the effect of drugs on G protein coupled receptor function in situ in brain tissue is not 43 reliably predicted from results in expression systems [3][4][5][6][7][8]. Therefore pharmacological 44 characterizations made in brain tissue likely relate better to behavioral outcomes than those made 45 in cell-based expression assays. 46Interest in the kappa opioid receptor (KOR) as a target for therapeutic development has 47 been growing consistently as clinical and preclinical studies have identified its role in aversive 48 behavioral states. KOR agonists produce profound adverse effects in humans, specifically 49 fatigue, sedation, confusion, impaired concentration, and anxiety. Furthermore at higher 50 concentrations visual and auditory hallucinations and feelings of depersonalization have been 51 reported [9,10]. Homologous effects have been described in animal models (reviewed in [11]). 52 Finally, blockade or genetic deletion of the KOR significantly reduces aversive responses to stress 53 [12-14], drug withdrawal [15-17], and pain [18], and has antidepres...

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Section: Discussionmentioning

confidence: 49%

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

Margolis

Wallace

Orden

et al. 2020

Preprint

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show abstract

Section: Plos Onementioning

confidence: 57%

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

et al. 2020

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Activation of the kappa opioid receptor (KOR) contributes to the aversive properties of stress, and modulates key neuronal circuits underlying many neurobehavioral disorders. KOR agonists directly inhibit ventral tegmental area (VTA) dopaminergic neurons, contributing to aversive responses (Margolis et al. 2003, 2006); therefore, selective KOR antagonists represent a novel therapeutic approach to restore circuit function. We used whole cell electrophysiology in acute rat midbrain slices to evaluate pharmacological properties of four novel KOR antagonists: BTRX-335140, BTRX-395750, PF-04455242, and JNJ-67953964. Each compound concentration-dependently reduced the outward current induced by the KOR selective agonist U-69,593. BTRX-335140 and BTRX-395750 fully blocked U-69,593 currents (IC50 = 1.2 ± 0.9 and 1.2 ± 1.3 nM, respectively). JNJ-67953964 showed an IC50 of 3.0 ± 4.6 nM. PF-04455242 exhibited partial antagonist activity asymptoting at 55% blockade (IC50 = 6.7 ± 15.1 nM). In 3/8 of neurons, 1 μM PF-04455242 generated an outward current independent of KOR activation. BTRX-335140 (10 nM) did not affect responses to saturating concentrations of the mu opioid receptor (MOR) agonist DAMGO or the delta opioid receptor (DOR) agonist DPDPE, while JNJ-67953964 (10 nM) partially blocked DAMGO and DPDPE responses. Importantly, BTRX-335140 (10 nM) rapidly washed out with complete recovery of U-69,593 responses within 10 min. Collectively, we show electrophysiological evidence of key differences amongst KOR antagonists that could impact their therapeutic potential and have not been observed using recombinant systems. The results of this study demonstrate the value of characterizing compounds in native neuronal tissue and within circuits implicated in the neurobehavioral disorders of interest.

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“…In both preclinical animal models and human imaging studies, KOR modulation of pain has been shown to be sex-dependent. In preclinical studies, intraplantar administration of U50 (100 µg/20µl) in males potentiated anti-hyperalgesic activity, as compared to females, suggesting a sex-dependent effect in the lateral sensitization rat model (Auh and Ro, 2012;Custodio-Patsey et al, 2020). Similarly administration of U50 increased tail withdrawal latency in male mice compared to female mice in tail withdrawal assay at 49ºC (Taylor et al, 2015).…”

Section: Discussionmentioning

confidence: 94%

Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

Madasu

Thang

Chilukuri

et al. 2020

Preprint

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Noxious cold sensation is commonly associated with peripheral neuropathies, however, there has been limited progress in understanding the mechanism of cold pain. Transient receptor potential (TRP) A1 channels facilitate the perception of noxious cold at the level of dorsal root ganglia (DRG), where kappa opioid receptors (KOR) are also expressed but have not previously been implicated in cold sensation. Here we identify a new role for KOR in enhancing cold hypersensitivity. First, we show that systemic KOR agonism (U50,488, KOR agonist), significantly potentiates the latency to jump and the number of jumps on the cold plate compared controls at 3°C. Importantly, NorBNI (KOR antagonist) attenuates U50,488-induced cold hypersensitivity. However, the central administration of NorBNI does not block U50,488-induced cold hypersensitivity suggesting that peripheral KOR likely modulate this effect. Furthermore, the peripherally-restricted KOR agonist, ff(nle)r-NH2 also induces cold hypersensitivity. Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 and TRPM8 channels in DRG. Finally, using calcium imaging in DRG, we show that intracellular calcium release is potentiated during the simultaneous application of a TRPA1 agonist, mustard oil (MO), and a KOR agonist (U50,488), when compared to MO alone. This potentiated calcium response is absent in TRPA1 KO mice. Together our data suggest that KOR-induces cold hypersensitivity through modulation of peripheral TRPA1 channels. These findings indicate that whether activation of peripheral KOR is protective or not may be dependent on the pain modality.

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Sex differences in kappa opioid receptor inhibition of latent postoperative pain sensitization in dorsal horn

Cited by 25 publications

References 79 publications

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

Differential effects of novel kappa opioid receptor antagonists on dopamine neurons using acute brain slice electrophysiology

Peripheral kappa opioid receptor activation drives noxious cold hypersensitivity in mice

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