Marco Carmignani1 Guido Valle2* Mario Stanislao3 Anna Rita Volpe11Department of Life, Health and Environmental Sciences, University of L’Aquila, Coppito, Italy
2Nuclear Medicine Unit, Scientific Institute “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy
3Cardiology Unit, Scientific Institute “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy
*Corresponding author: Valle G, Nuclear Medicine Unit, Scientific Institute “Casa Sollievo della Sofferenza”, San Giovanni Rotondo, Italy, E-mail: firstname.lastname@example.org
Article Type: Letter to Editor
Citation: Carmignani M, Valle G, Stanislao M, Volpe AR (2016) Towards the Resurrection of the DeltaOpioid Receptor Antagonists in Haemodynamic Shock Management? J Clin Anesth Manag 1(4): doi http://dx.doi.org/10.16966/2470-9956.113
Copyright: © 2016 Carmignani M, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
We refer to the papers by Liu et al.  and by Duranteau and Le Manach  appeared on Anesthesiology, dealing with the suitable employment of the δ-opioid receptor antagonist ICI 174864 (N,N, diallyl-tyr-aibaib-phe-leu-OH) in experimental haemorrhagic shock and of δ-opioid receptor antagonists for “buying time” in haemorrhagic shock patients, respectively.
These studies follow what shown by ours in 2005  in rabbits developing hypodynamic systemic shock when the superior mesenteric artery (SMA) was hypoperfused at critical levels representing 25-20% of its mean baseline blood flow. We showed that the selective blockade of cardiovascular δ-opioid receptors by ICI 174864 or naltrindole improved haemodynamics, prevented shock irreversibility and reduced plasma nitric oxide (NO) levels; similar effects were obtained by selective inhibition of inducible NO synthase (iNOS) by AMT ( ± 2-amino-5,6-dihydro- 6-methyl-4H-1,3-thiazine, HCl) but not by blocking opioid receptors other than the δ ones (e.g. the κ1-receptors by nor-binaltorphimine) or by using drugs like fenoprofen and hydrocortisone . Moreover, leu5- and met5-enkephalins (ENK, specific activators of δ-opioid receptors), but not other physiological agonists, impaired haemodynamic function and increased plasma NO levels, when administered intravenously, much more during SMA hypoperfusion (SMAH) than in baseline conditions . Considering that splanchnic artery hypoperfusion had been suggested to play a significant role for the development of haemodynamic shock irreversibility, our experimental model was just assessed to establish the critical levels at which SMAH by itself could induce haemodynamic shock. In addition, splanchnic artery occlusion-reperfusion shock models were thought to not reproduce the cardiac depression and/or local arterial vasoconstriction determining splanchnic hypoperfusion during various forms of systemic shock. We found the above effects of SMAH to depend on ENK release from the gut causing hyperactivation of the cardiovascular  δ-opioid receptors which, in turn, led to high plasma levels of NO. This plasma NO increase, promoving haemodynamic derangement and shock irreversibility, was explained by both δ-opioid receptor-induced higher iNOS activity and ENK-induced inhibition of kininase II [degrading bradykinin (BK) to inactive peptide] but not of kininase I . In this regard, we demonstrated that BK supplies, following action of kininase I, its C-terminal L-arginine for endothelial NO synthesis  and that NO-mediated ENK interactions with the renin-angiotensin and kallikrein-kinin systems play an important role in modulating arterial vasoconstriction and venous dilatation [5-7]. Therefore, we pointed out to be not surprising that the δ1,2-opioid receptor agonist DADLE (D-ala2, D-leu5 -enkephalin) could be ineffective either in a rat model of lethal haemmorrhagic shock, probably depending on the severe and protracted intestinal hypoperfusion, or in reducing cerebral focal or global ischaemia-reperfusion damage [8,9]. On the other hand, pharmacological plasma concentrations of opioid agonists originate a lot of complex interactions with neurotransmitters, neuromodulators, autacoids, ion channels and transduction pathways allowing to eclipse the physiological effects of opioid peptides [9,10]. Since pronounced splanchnic artery hypoperfusion occurs in all advanced systemic shock states, we concluded that selective δ-opioid receptor antagonists and/or iNOS inhibitors may prove to be useful in improving shock haemodynamics and metabolic derangement and/or in preventing progression toward shock irreversibility .
Side effects and safeness of the clinical handling of ICI 174864 and other selective δ-opioid receptor antagonists as well as of selective iNOS inhibitors remain to be characterized. The only study on this issue is the paper by Long et al.  reporting the occurrence of neurological adverse effects in ICI 174864-treated rats so that these Authors conclude for a potential limitation on the clinical employment of such compound . However, the efficacy of δ-opioid receptor antagonists and/or selective iNOS inhibitors in experimental haemodynamic shock models lets reasonably hope that these classes of drugs might result life-saving in an often deadly condition as shock is. Therefore, particular consideration should be addressed to a prompt clinical experimentation targeting the δ-opioid receptor/NO pathway with such kind of drugs in shock patients.
- Liu L, Tian K, Zhu Y, Ding X, Li T (2013) δ-opioid receptor antagonist, ICI 174,864, is suitable for the early treatment of uncontrolled hemorrhagic shock in rats. Anesthesiology 119: 379-388. [Ref.]
- Duranteau J, Le Monach Y (2013) δ-opioid receptor antagonists: do they buy time for traumatic hemorrhagic shock patients? Anesthesiology 119: 253-255. [Ref.]
- Carmignani M, Zucchetti F, Sacco R, Bolognini S, Volpe AR (2005) Shock induction by arterial hypoperfusion of the gut involves synergistic interactions between the peripheral enkephalin and nitric oxide systems. Int J Immunopathol Pharmacol 18: 33-48. [Ref.]
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- Carmignani M, Volpe AR (1990) Interactions among leu5- enkephalin, kallikrein-kinin and renin-angiotensin systems in the heart and in the kidney: Haemodynamic consequences. Eur J Pharmacol 183: 1152. [Ref.]
- Carmignani M, Volpe AR (1996) Nitric oxide and delta-opioid receptors in the tissue interactions among enkephalins, angiotensins and kinins. Immunopharmacology 32: 172-176. [Ref.]
- Volpe AR, Fontecchio G, Carmignani M (1999) Regulatory role of bradykinin in the coronaric and cerebral circulations and in systemic hemodynamics. Immunopharmacology 44: 87-92. [Ref.]
- Drabek T, Han F, Garman RH, Stezoski J, Tisherman SA, et al. (2008) Assessment of the delta-opioid agonist DADLE in a rat model of lethal hemorrhage treated by emergency preservation and resuscitation. Resuscitation 77: 220-228. [Ref.]
- Carmignani M, Volpe AR, Stanislao M, Valle G (2009) Delta-opioid receptor ligands in shock treatment. Resuscitation 80: 1330-1331. [Ref.]
- Long JB, Ruvio BA, Glatt CE, Holaday JW (1984) ICI 174864, a putative δ-opioid antagonist, reverses endotoxemic hypotension: Pretreatment with dynorphin 1-13, a κ agonist, blocks this action. Neuropeptides 5: 291-294. [Ref.]
- Long JB, Petras JM, Holaday JW (1988) Neurologic deficits and neuronal injury in rats resulting from non-opioid actions of the delta receptor antagonist ICI 174864. J Pharmacol Exp Ther 244: 1169- 1177. [Ref.]
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