κ-Opioid receptor antisense oligonucleotide injected into rat hippocampus causes hypertension

Wright, Rebecca C; McConnaughey, Mona M.; Phan, Tu; Ingenito, Alphonse J.

doi:10.1016/s0014-2999(99)00410-0

Cited by 12 publications

(6 citation statements)

References 19 publications

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“…Antisense ODNs targeting the KOR have been shown to selectively inhibit -ORA antinociception in rats (Adams et al, 1994) and, more recently, to cause hypertension after injection into the hippocampus (Wright et al, 1999). Intrathecal administration of antisense ODNs has also been demonstrated to cause a knockdown of peripheral proteins.…”

Section: Antisense Strategies In Opioid Pharmacologymentioning

confidence: 99%

κ-Opioid Receptor Agonists Modulate Visceral Nociception at a Novel, Peripheral Site of Action

Joshi

Porreca

et al. 2000

J. Neurosci.

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kappa-opioid receptor agonists (kappa-ORAs) have been shown to modulate visceral nociception through an interaction with a peripheral, possibly novel, kappa-opioid-like receptor. We used in the present experiments an antisense strategy to further explore the hypothesis that kappa-ORA effects in the colon are produced at a site different from the cloned kappa-opioid receptor (KOR). An antisense oligodeoxynucleotide (ODN) to the cloned rat KOR was administered intrathecally (12.5 microg, twice daily for 4 d) to specifically knock-down the cloned KOR. Efficacy of the KOR antisense ODN treatment was behaviorally evaluated by assessing the antinociceptive effects of peripherally administered kappa- (EMD 61, 753 and U 69,593), mu- (DAMGO) and delta- (deltorphin) ORAs in the formalin test. Intrathecal antisense, but not mismatch ODN blocked the actions of EMD 61,753 and U 69,593 without affecting the actions of DAMGO or deltorphin; a complete recovery of antinociceptive actions of the kappa-ORA EMD 61,753 was observed 10 d after the termination of antisense ODN treatment. In contrast, the ability of EMD 61,753 to dose-dependently attenuate responses of pelvic nerve afferent fibers to noxious colonic distension was unaffected in the same rats in which the antisense ODN effectively knocked-down the KOR as assessed in the formalin test. Additionally, Western blot analysis demonstrated a significant downregulation of KOR protein in the L4-S1 dorsal root ganglia of antisense, but not mismatch ODN-treated rats. The present results support the existence of a non-kappa-opioid receptor site of action localized in the colon.

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Section: Antisense Strategies In Opioid Pharmacologymentioning

confidence: 99%

κ-Opioid Receptor Agonists Modulate Visceral Nociception at a Novel, Peripheral Site of Action

Joshi

Porreca

et al. 2000

J. Neurosci.

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“…Fluctuations in circulating adrenal steroids during stress represent another important influence on prepro‐NPY mRNA expression in the hippocampus, particularly in the dentate gyrus (17, 57). Furthermore, the hippocampus has been implicated in learning and memory (14, 58), behaviour and emotion (59) and cardiovascular control (60), suggesting that these functions may be influenced by differences in the NPY response to restraint at the level of the hippocampus and dentate gyrus in SHR.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Acute and Chronic Restraint on the Central Expression of Prepro‐Neuropeptide Y mRNA in Normotensive and Hypertensive Rats

Sweerts

Jarrott

Lawrence

2001

J Neuroendocrinology

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Neuropeptide Y (NPY), one of the most abundant neuropeptides found in the central nervous system (CNS), has been implicated in the regulation of many autonomic functions, including cardiovascular control and the central stress response. The present study represents a detailed investigation of the effects of acute and chronic restraint stress on the expression of the mRNA encoding the NPY precursor, prepro-NPY, in the CNS of normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) using in situ hybridization histochemistry. Basal (unstressed) levels of prepro-NPY mRNA expression were found to be significantly increased in the hypothalamic arcuate nucleus of SHR compared to WKY rats, with similar levels of prepro-NPY mRNA expression found in the remaining central nuclei. Following exposure to both acute and chronic restraint, significant changes in prepro-NPY mRNA expression were found in a variety of central regions in both strains, including the arcuate nucleus and hippocampus (both strains), medial amygdala and cortex (WKY only), and dentate gyrus, nucleus of the solitary tract and ventrolateral medulla (SHR only). A comparison of the temporal response to restraint revealed that significant differences between strains existed in regions such as the arcuate nucleus, hippocampus and dentate gyrus, providing further evidence that hypertensive rats apparently have an impaired neural stress response. The present study demonstrates that exposure to restraint results in significant changes in prepro-NPY mRNA expression in specific nuclei of both WKY and SHR that are components of not only the central circuitry regulating the stress response, but also the neural network modulating autonomic function.

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“…Destruction of the dynorphin-producing cells of the dentate gyrus by colchicine induces hypertension in the WKY rat and accelerates its development in SHR (12). More recently we were able to show that an antisense oligonucleotide directed against the kappa receptor, when microinjected bilaterally into the hippocampus, induced hypertension in WKY rats and increased arterial blood pressure in SHR (13). Furthermore, we have shown that microinfusions of both dynorphins and non-peptide kappa agonists into rat hippocampus lower MAP and HR in both SHR and WKY (more so in SHR) (14,15).…”

Section: Introductionmentioning

confidence: 93%

Chronic Blockade of Hippocampal Kappa Receptors Increases Arterial Pressure in Conscious Spontaneously Hypertensive Rats but Not in Normotensive Wistar Kyoto Rats

Shen

Ingenito

2000

Clinical and Experimental Hypertension

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Previous studies in this laboratory have shown that dynorphins acting on hippocampal kappa opioid receptors in rat brain exert a restraining influence on arterial blood pressure and that a relative deficiency of their production in the spontaneously hypertensive rat (SHR) may be involved in SHR hypertension. Kappa receptor blockade should therefore exacerbate hypertension in SHR. We explored the latter possibility by chronic unilateral infusion of nor-binaltorphimine dihydrochloride (nor-BNI), a selective kappa receptor antagonist, into the right dorsal hippocampus of conscious SHR and normotensive Wistar-Kyoto (WKY) controls over a 14 day period. Additional controls consisted of similar hippocampal infusions of equivalent volumes of drug vehicle in both rat strains. Mean arterial pressure (MAP) and heart rates (HR) were determined in each animal once daily by the tail cuff method during this period. Nor-BNI induced a sustained increase in the basal high level of MAP in SHR from 132 +/- 8 to 150 +/- 10 mmHg throughout the 14 days and an increased HR from 427 +/- 17 to 477 +/- 30 on day 3 to 5 following the drug. By contrast, nor-BNI had no significant effects on either MAP or HR in WKY rats and control infusions of drug vehicle were similarly without effect in both strains. The results support our previous suggestion that the kappa opioid system of the hippocampus ordinarily restrains arterial blood pressure in SHR since prolonged hippocampal kappa receptor blockade results in augmented hypertension in this strain.

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κ-Opioid receptor antisense oligonucleotide injected into rat hippocampus causes hypertension

Cited by 12 publications

References 19 publications

κ-Opioid Receptor Agonists Modulate Visceral Nociception at a Novel, Peripheral Site of Action

κ-Opioid Receptor Agonists Modulate Visceral Nociception at a Novel, Peripheral Site of Action

The Effect of Acute and Chronic Restraint on the Central Expression of Prepro‐Neuropeptide Y mRNA in Normotensive and Hypertensive Rats

Chronic Blockade of Hippocampal Kappa Receptors Increases Arterial Pressure in Conscious Spontaneously Hypertensive Rats but Not in Normotensive Wistar Kyoto Rats

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