Dissociable effects of the kappa opioid receptor agonist nalfurafine on pain/itch-stimulated and pain/itch-depressed behaviors in male rats

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Abstract

<div class="section"> <a class="named-anchor" id="S1">  </a> <h5 class="section-title" id="d723624e151">Rationale</h5> <p id="P1">Nalfurafine is a G-protein-signaling-biased kappa opioid receptor (KOR) agonist approved in Japan for second-line treatment of uremic pruritus. Neither nalfurafine nor any other KOR agonist is currently approved anywhere for treatment of pain, but recent evidence suggests that G-protein-signaling-biased KOR agonists may have promise as candidate analgesics/antipruritics with reduced side effects compared to nonbiased or β-arrestin-signaling-biased KOR agonists. </p> </div><div class="section"> <a class="named-anchor" id="S2">  </a> <h5 class="section-title" id="d723624e156">Objectives</h5> <p id="P2">This study compared nalfurafine effects in rats using assays of pain-stimulated and pain-depressed behavior used previously to evaluate other candidate analgesics. Nalfurafine effects were also examined in complementary assays of itch-stimulated and itch-depressed behavior. </p> </div><div class="section"> <a class="named-anchor" id="S3">  </a> <h5 class="section-title" id="d723624e161">Methods</h5> <p id="P3">Intraperitoneal lactic acid (IP acid) and intradermal serotonin (ID 5HT) served as noxious and pruritic stimuli, respectively, in male Sprague Dawley rats to stimulate stretching (IP acid) or scratching (ID 5HT) or to depress positively reinforced operant responding in an assay of intracranial self-stimulation (ICSS; both stimuli). </p> </div><div class="section"> <a class="named-anchor" id="S4">  </a> <h5 class="section-title" id="d723624e166">Results</h5> <p id="P4">Nalfurafine was equipotent to decrease IP acid-stimulated stretching and ID 5HT-stimulated scratching; however, doses of nalfurafine that decreased these pain/itch-stimulated behaviors also decreased control ICSS performance. Moreover, nalfurafine failed to alleviate either IP acid- or ID 5HT-induced depression of ICSS. </p> </div><div class="section"> <a class="named-anchor" id="S5">  </a> <h5 class="section-title" id="d723624e171">Conclusions</h5> <p id="P5">These results suggest that nalfurafine-induced decreases in pain/itch-stimulated behaviors may reflect nonselective decreases in motivated behavior rather than analgesia or antipruritus against the noxious and pruritic stimuli used here. This conclusion agrees with the absence of clinical data for nalfurafine analgesia and the weak clinical data for nalfurafine antipruritus. Nalfurafine bias for G-protein signaling may not be sufficient for clinically safe and reliable analgesia or antipruritus. </p> </div>

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The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo.

Kate L White, J Robinson, Hu Zhu … (2015)

The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein-biased agonists have not been available to test this idea. Here we provide data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas β-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein-biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein-biased KOR agonists.

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Inflammation-induced decrease in voluntary wheel running in mice: a nonreflexive test for evaluating inflammatory pain and analgesia.

Enrique Cobos, Nader Ghasemlou, Dioneia Araldi … (2012)

Inflammatory pain impacts adversely on the quality of life of patients, often resulting in motor disabilities. Therefore, we studied the effect of peripheral inflammation induced by intraplantar administration of complete Freund's adjuvant (CFA) in mice on a particular form of voluntary locomotion, wheel running, as an index of mobility impairment produced by pain. The distance traveled over 1 hour of free access to activity wheels decreased significantly in response to hind paw inflammation, peaking 24 hours after CFA administration. Recovery of voluntary wheel running by day 3 correlated with the ability to support weight on the inflamed limb. Inflammation-induced mechanical hypersensitivity, measured with von Frey hairs, lasted considerably longer than the impaired voluntary wheel running and is not driving; therefore, the change in voluntary behavior. The CFA-induced decrease in voluntary wheel running was dose-dependently reversed by subcutaneous administration of antiinflammatory and analgesic drugs, including naproxen (10-80 mg/kg), ibuprofen (2.5-20mg/kg), diclofenac (1.25-10mg/kg), celecoxib (2.5-20mg/kg), prednisolone (0.62-5mg/kg), and morphine (0.06-0.5mg/kg), all at much lower doses than reported in most rodent models. Furthermore, the doses that induced recovery in voluntary wheel running did not reduce CFA-induced mechanical allodynia, indicating a greater sensitivity of the former as a surrogate measure of inflammatory pain. We conclude that monitoring changes in voluntary wheel running in mice during peripheral inflammation is a simple, observer-independent objective measure of functional changes produced by inflammation, likely more aligned to the global level of pain than reflexive measures, and much more sensitive to analgesic drug effects. Copyright Â© 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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Depressive-like effects of the kappa-opioid receptor agonist salvinorin A on behavior and neurochemistry in rats.

William Carlezon, Robin R Richards, Lucia B. Rothman-Denes … (2005)

Endogenous opioids seem to play a critical role in the regulation of mood states. For example, there is accumulating evidence that stimulation of kappa-opioid receptors, upon which the endogenous opioid dynorphin acts, can produce depressive-like behaviors in laboratory animals. Here we examined whether systemic administration of salvinorin A (SalvA), a potent and highly selective kappa-opioid agonist, would produce depressive-like effects in the forced swim test (FST) and intracranial self-stimulation (ICSS) test, which are behavioral models often used to study depression in rats. We extracted, isolated, and purified SalvA from Salvia divinorum plant leaves and examined its effects on behavior in the FST and ICSS test across a range of doses (0.125-2.0 mg/kg) after systemic (intraperitoneal) administration. SalvA dose dependently increased immobility in the FST, an effect opposite to that of standard antidepressant drugs. Doses of SalvA that produced these effects in the FST did not affect locomotor activity in an open field. Furthermore, SalvA dose dependently elevated ICSS thresholds, an effect similar to that produced by treatments that cause depressive symptoms in humans. At a dose that caused the depressive-like effects in both the FST and ICSS assays, SalvA decreased extracellular concentrations of dopamine (DA) within the nucleus accumbens (NAc), a critical component of brain reward circuitry, without affecting extracellular concentrations of serotonin (5-HT). These data provide additional support for the hypothesis that stimulation of brain kappa-opioid receptors triggers depressive-like signs in rats and raise the possibility that decreases in extracellular concentrations of DA within the NAc contribute to these effects.