Psychotomimesis Mediated by κ Opiate Receptors

Pfeiffer, Andreas F. H.; Brantl, Victor; Herz, A.; Emrich, H. M.

doi:10.1126/science.3016896

Cited by 787 publications

(588 citation statements)

References 20 publications

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“…However, opiate exposure increases both dynorphin expression and that of its cognate receptor, KOR. Thus, in addition to MOR signaling, KOR pathways are also stimulated by these drugs, and have been shown to mediate, depressive and dysphoric states in these individuals (Pfeiffer et al, 1986 andCarlezon et al, 1998) and in Dyn−/− mice (Wittmann et al, 2009). As outlined herein, such an opiate-mediated increase in dynorphin signaling would also act to stimulate NPY expression within the hypothalamus and with it suppression of bone formation.…”

Section: Discussionmentioning

confidence: 81%

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The endogenous opioid dynorphin is required for normal bone homeostasis in mice

et al. 2012

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Chronic opiate usage, whether prescribed or illicit, has been associated with changes in bone mass and is a recognized risk factor for the development of osteoporosis; however, the mechanism behind this effect is unknown. Here we show that lack of dynorphin, an endogenous opioid, in mice (Dyn−/−), resulted in a significantly elevated cancellous bone volume associated with greater mineral apposition rate and increased resorption indices. A similar anabolic phenotype was evident in bone of mice lacking dynorphin's cognate receptor, the kappa opioid receptor. Lack of opioid receptor expression in primary osteoblastic cultures and no change in bone cell function after dynorphin agonist treatment in vitro indicates an indirect mode of action. Consistent with a hypothalamic action, central dynorphin signaling induces extracellular signal-regulated kinase (ERK) phosphorylation and c-fos activation of neurons in the arcuate nucleus of the hypothalamus (Arc). Importantly, this signaling also leads to an increase in Arc NPY mRNA expression, a change known to decrease bone formation. Further implicating NPY in the skeletal effects of dynorphin, Dyn−/−/NPY−/− double mutant mice showed comparable increases in bone formation to single mutant mice, suggesting that dynorphin acts upstream of NPY signaling to control bone formation. Thus the dynorphin system, acting via NPY, may represent a pathway by which higher processes including stress, reward/addiction and depression influence skeletal metabolism. Moreover, understanding of these unique interactions may enable modulation of the adverse effects of exogenous opioid treatment without directly affecting analgesic responses.

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Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

The endogenous opioid dynorphin is required for normal bone homeostasis in mice

et al. 2012

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“…These results suggest that repeated stress exposure induced the release of endogenous dynorphins that activate kappa opioid receptors and subsequently enhanced the rewarding properties of cocaine. As kappa receptor activation is aversive in rats (Shippenberg and Herz 1986) and produces dysphoria in humans (Pfeiffer et al 1986), we rationalize these results by hypothesizing that the dysphoria produced by stressinduced dynorphin release enhances the rewarding properties by increasing the euphorigenic valence of cocaine.…”

Section: Introductionmentioning

confidence: 85%

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

2008

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Introduction-Prior activation of the kappa opioid system by repeated stress or agonist administration has been previously shown to potentiate the rewarding properties of subsequently administered cocaine. In the present study, intermittent and uncontrollable footshock, a single session of forced swim, or acute administration of the kappa agonist U50,488 (5 mg/kg) were found to reinstate place preference in mice previously conditioned with cocaine (15 mg/kg) and subsequently extinguished by repeated training sessions without drug.

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“…There is emerging experimental evidence that delta and kappa opioid receptors can provide plausible alternative targets for alleviating painful diabetic neuropathy [46] and recent clinical trials with oxycodone, a mixed mu and kappa opioid receptor agonist [47,48] also support this approach. Asimadoline may provide a local therapeutic approach to treating diabetic painful neuropathy that avoids the sedation and dysphoria occurring with KOR agonists that penetrate the central nervous system [49] and also avoids the respiratory depression and potential for abuse associated with mu opioid agonists [50].…”

Section: Discussionmentioning

confidence: 99%

Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats

et al. 2006

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Aims/hypothesis We investigated spinal and peripheral kappa opioid systems in diabetic rats. Materials and methods Dynorphin A, N-methyl-D-aspartate (NMDA) and kappa opioid receptor (KOR) were measured in spinal cord, dorsal root ganglia, peripheral nerves and foot skin of control and streptozotocin-induced diabetic rats by immunoassay and Western blotting. Behavioural assessments of paw tactile sensitivity and formalin-evoked hyperalgesia were performed in normal and diabetic rats before and after treatment with asimadoline. Results Dynorphin A protein levels were significantly increased in peripheral nerves and footpad skin of diabetic rats. Dynorphin A exhibits both anti-and pro-nociceptive properties depending on activation of either KOR or NMDA receptors. Spinal protein levels of these receptors were not changed by diabetes, while KOR levels in the sciatic and peroneal nerves were significantly increased. Exploiting the presence and elevated levels of KOR in the periphery, we investigated the effect of the peripheral KOR agonist asimadoline on formalin-evoked hyperalgesia and tactile allodynia in diabetic rats. Both formalin-evoked hyperalgesia and tactile allodynia in diabetic rats were acutely ameliorated by asimadoline. To confirm that the effect of asimadoline was related to its property as KOR agonist, diabetic rats were pretreated with the selective KOR antagonist nor-binaltorphimine. Intraplantar norbinaltorphimine abolished the ability of asimadoline to alleviate tactile allodynia in diabetic rats. Systemic and intrathecal nor-binaltorphimine partially inhibited the effect of asimadoline against formalin-evoked hyperalgesia in diabetic rats. Conclusions/interpretation Using selective peripheral KOR agonists to take advantage of elevated peripheral KOR expression may provide a novel therapeutic approach for painful diabetic neuropathy.

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Psychotomimesis Mediated by κ Opiate Receptors

Cited by 787 publications

References 20 publications

The endogenous opioid dynorphin is required for normal bone homeostasis in mice

The endogenous opioid dynorphin is required for normal bone homeostasis in mice

Stress-induced reinstatement of cocaine seeking is mediated by the kappa opioid system

Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in streptozotocin-induced diabetic rats

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