Opioid Peptides: Simultaneous δ Agonism and μ Antagonism in Somatostatin Analogues

Bonner, G. Gregg; Davis, Peg; Stropova, Dagmar; Ferguson, R. D.; Yamamura, Henry I.; Porreca, Frank; Hruby, Victor J.

doi:10.1016/s0196-9781(96)00242-2

Cited by 25 publications

(33 citation statements)

References 36 publications

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“…The other notable finding of the present work is that CTAP, previously considered to be a neutral -opioid receptor antagonist based on in vivo and in vitro observations using other systems (Bonner et al, 1997;Sterious and Walker, 2003), enhanced FSK-stimulated AC activity (Figs. 2-4).…”

Section: Dual Effects Of Damgo and Ctap On Adenylyl Cyclase 259supporting

confidence: 67%

“…The present study investigates inverse agonist properties of a commonly used -opioid receptor (MOR) antagonist, D-PheCys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP). Although previously characterized as a neutral antagonist in vivo (Bonner et al, 1997;Sterious and Walker, 2003) and in GH 3 cells ), the present study reveals that it manifests inverse agonism in Chinese hamster ovary (CHO) cells stably transfected with the -opioid receptor (MOR-CHO), underscoring the plasticity of inverse agonist responsiveness and its dependence on local cellular factors. Additionally, use of two bacterial toxins commonly used to assess receptor G protein coupling, pertussis toxin (PTX) and cholera toxin (CTX), provides further pharmacological evidence for -opioid receptor coupling to G s and augmented -opioid receptorcoupled signaling via the G ␤␥ subunit after chronic morphine.…”

mentioning

confidence: 58%

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Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

Szücs¹,

Boda²,

Gintzler³

2004

J Pharmacol Exp Ther

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The -opioid receptor (MOR) couples to multiple G proteins, of which coupling to G s has long been debated. As expected, in opioid naive Chinese hamster ovary cells expressing recombinant MOR, the predominant action of [D-Ala 2 ,N-Me-Phe 4 ,Gly 5 -ol]-enkephalin (DAMGO) is inhibitory. However, inactivation of G i /G o proteins via pertussis toxin (PTX) unmasks its ability to facilitate forskolin activation of adenylyl cyclase (AC) activity. Tolerance develops to this effect of DAMGO, which can also be attenuated by cholera toxin (CTX). The latter suggests G s mediation. D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH 2 (CTAP), previously considered to be a neutral MOR antagonist, also produces a facilitation of forskolin (FSK) activation of AC that is augmented by chronic morphine. Facilitative effects of CTAP in naive as well as its augmentation in tolerant membranes are both substantially reduced by CTX. This suggests that not only G s mediation but also G s␣ -linked signaling is critical to the chronic morphine-induced enhanced facilitative action of CTAP. Interestingly, the (augmented) CTAP facilitation of FSKstimulated AC activity that is observed in opioid tolerant (but not in naive) membranes is also sensitive to PTX. This can best be explained by postulating the involvement of G i -derived G ␤␥ , which would stimulate type 2 ACs, conditional on the presence of activated G s␣ . The emergence of a G ␤␥ dimension of AC stimulation by CTAP after chronic morphine could explain its ability to augment the stimulatory action of CTAP on AC. These results support putative MOR coupling to G s and underscore the multifaceted nature and plasticity of MOR G protein coupling.Traditionally, ligands acting on a G protein-coupled receptor (GPCR) are classified as either agonists, partial agonists, or antagonists. Recent findings, however, suggest that several compounds traditionally considered to be competitive (neutral) antagonists at GPCRs that are physiologically expressed at a low level can exhibit inverse agonist properties, i.e., have negative intrinsic activity (signaling efficacy) when these receptors and/or their cognate G proteins are present at higher levels of expression (Costa and

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Section: Dual Effects Of Damgo and Ctap On Adenylyl Cyclase 259supporting

confidence: 67%

mentioning

confidence: 58%

Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

Szücs¹,

Boda²,

Gintzler³

2004

J Pharmacol Exp Ther

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“…It should be considered that these drugs, at higher doses, may lose their selectivity and/or have agonistic activity for one type of receptor and antagonistic activity for other type. There is at least one study that shows that CTAP analogs can have simultaneous ␦-agonist and -antagonist activities at high doses (9). We show here that, even when we submit the animals to lower ambient temperatures, thus facilitating heat loss (as observed after propranolol administration), the -opioid antagonist does not cause a hypothermic effect at low doses.…”

Section: Discussionmentioning

confidence: 63%

Endogenous opioids: role in prostaglandin-dependent and -independent fever

Fraga

Machado²,

Fernandes³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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This study evaluated the participation of -opioid-receptor activation in body temperature (T b) during normal and febrile conditions (including activation of heat conservation mechanisms) and in different pathways of LPS-induced fever. The intracerebroventricular treatment of male Wistar rats with the selective opioid -receptor-antagonist cyclic D-Phe-Cys-Try-DTrp-Arg-Thr-Pen-Thr-NH2 (CTAP; 0.1-1.0 g) reduced fever induced by LPS (5.0 g/kg) but did not change Tb at ambient temperatures of either 20°C or 28°C. The subcutaneous, intracerebroventricular, and intrahypothalamic injection of morphine (1.0 -10.0 mg/kg, 3.0 -30.0 g, and 1-100 ng, respectively) produced a dose-dependent increase in Tb. Intracerebroventricular morphine also produced a peripheral vasoconstriction. Both effects were abolished by CTAP. CTAP (1.0 g icv) reduced the fever induced by intracerebroventricular administration of TNF-␣ (250 ng), IL-6 (300 ng), CRF (2.5 g), endothelin-1 (1.0 pmol), and macrophage inflammatory protein (500 pg) and the first phase of the fever induced by PGF2␣ (500.0 ng) but not the fever induced by IL-1␤ (3.12 ng) or PGE2 (125.0 ng) or the second phase of the fever induced by PGF2␣. Morphine-induced fever was not modified by the cyclooxygenase (COX) inhibitor indomethacin (2.0 mg/kg). In addition, morphine injection did not induce the expression of COX-2 in the hypothalamus, and CTAP did not modify PGE2 levels in cerebrospinal fluid or COX-2 expression in the hypothalamus after LPS injection. In conclusion, our results suggest that LPS and endogenous pyrogens (except IL-1␤ and prostaglandins) recruit the opioid system to cause a -receptor-mediated fever. prostaglandin independent; body temperature; morphine; CTAP THE REGULATION OF BODY TEMPERATURE (T b ) is under the control of a hierarchy of neuronal structures that must first integrate afferent and central information before activating appropriate physiological and behavioral responses. In mammals, T b is regulated with considerable precision, normally varying by only a few degrees Celsius. This is an important adaptation because most biochemical and physiological processes are temperature dependent. In some conditions, adjustments of T b are beneficial. During infection, an increase in T b (fever) enhances immunologic responses and facilitates recovery and survival of an individual (34). In other conditions (such as during hypoxia), a decrease in T b is also beneficial because lower T b increases survival, primarily through a reduction in metabolic rate (13,38). The preoptic area of anterior hypothalamus (POA-AH) is one of the major neuronal structures involved in the control of T b . In addition to receiving afferent input from peripheral thermoreceptors, the POA-AH responds to central changes in hypothalamic temperature (10).Fever is characterized as a controlled elevation in the thermal set point, which is induced initially by exogenous pyrogens. These exogenous pyrogens induce the synthesis and release of a number of endogenous pyrogens, including IL-1␤, TNF...

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“…Solutions of -conotoxin GVIA and -agatoxin TK (Alomone Labs, Jerusalem, Israel) were prepared at their final concentration in HEPES buffer on the day of use. Based on the literature, the lowest concentration tested for each opioid antagonist was selective for one receptor subtype (Pelton et al, 1986;Portoghese et al, 1990;Bonner et al, 1997;Ananthan et al, 1998). The calcium channel blockers were used at concentrations reported to be effective and selective in blocking VDCCs in DRG neurons in vitro (Cardenas et al, 1997;Endoh and Suzuki, 1998;Formenti et al, 1998).…”

Section: Methodsmentioning

confidence: 99%

“…Evidence for involvement of MORs includes blockade of the effect of morphine by CTAP at a concentration that selectively inhibits MORs (Bonner et al, 1997) and blockade by naltrindole at a concentration that blocks MORs and DORs (Portoghese et al, 1991;Raynor et al, 1994). Furthermore, DAMGO mimicked the effect of morphine at a concentration that selectively binds receptors (Erspamer et al, 1989).…”

Section: Opioid Receptor Pharmacologymentioning

confidence: 99%

Differential Effects of CB1 and Opioid Agonists on Two Populations of Adult Rat Dorsal Root Ganglion Neurons

Khasabova

Harding-Rose

Simone³

et al. 2004

J. Neurosci.

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Opioid Peptides: Simultaneous δ Agonism and μ Antagonism in Somatostatin Analogues

Cited by 25 publications

References 36 publications

Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

Endogenous opioids: role in prostaglandin-dependent and -independent fever

Differential Effects of CB1 and Opioid Agonists on Two Populations of Adult Rat Dorsal Root Ganglion Neurons

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Opioid Peptides: Simultaneous δ Agonism and μ Antagonism in Somatostatin Analogues

Cited by 25 publications

References 36 publications

Dual Effects of DAMGO [d-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor GsCoupling

Dual Effects of DAMGO [d-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor GsCoupling

Endogenous opioids: role in prostaglandin-dependent and -independent fever

Differential Effects of CB1 and Opioid Agonists on Two Populations of Adult Rat Dorsal Root Ganglion Neurons

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Resources

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Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling

Dual Effects of DAMGO [d-Ala²,N-Me-Phe⁴,Gly⁵-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂) on Adenylyl Cyclase Activity: Implications for μ-Opioid Receptor G_sCoupling