Naloxone HCl

KD: 13.1 nM for opioid receptor

An opioid antagonist, or opioid receptor antagonist, is a receptor antagonist acting on opioid receptors. Naloxone is commonly used opioid antagonist drug which is a competitive antagonist binding to the opioid receptors with higher affinity than agonists but does not activate the receptors.

In vitro: Naloxone is a non-selective opioid antagonist for the μ-, δ- and κ-opioid receptors. Naloxone competitively inhibits the pharmacologic effects of opioids and, with the classical receptor theory, produces a parallel right shift in the dose-response curves of opioids [1].

In vivo: (or HAD line). Rats of the High Alcohol Drinking (HAD) line were treated with naloxone. Naloxone suppressed water intake when water was presented as the sole source of fluid. In contrast, naloxone produced a dose-dependently decrease in ethanol consumption, without altering water intake. The results suggest activation of the endogenous opioid system may be an important mechanism which serves to maintain continued ethanol drinking [3].

Clinical trial: Naloxone, also known as Narcan among other names, is a medication used to reverse the effects of opioids especially in overdose. The drug was approved for opioid overdose by Food and Drug Administration in 1971.

Reference:
[1] van Dorp E, Yassen A, Dahan A.  Naloxone treatment in opioid addiction: the risks and benefits. Expert Opin Drug Saf. 2007 Mar;6(2):125-32.
[2] Froehlich JC, Harts J, Lumeng L, Li TK.  Naloxone attenuates voluntary ethanol intake in rats selectively bred for high ethanol preference. Pharmacol Biochem Behav. 1990 Feb;35(2):385-90.

Narcan (naloxone HCl).[Pubmed:2288924]

Gastroenterol Nurs. 1990 Winter;12(3):193-5.

The gastroenterology nurse must be familiar with the use of Narcan. Narcan is frequently administered in the endoscopy suite after the procedure for the reversal of narcotic depression induced by pre-procedure intravenous sedation. Knowledge of Narcan will allow the nurse to safely administer the medication as well as adequately assess the patient's response to it.

Effects of naloxone-HCl on cortisol levels in patients with affective disorder and normal controls.[Pubmed:6943595]

Psychiatry Res. 1981 Jun;4(3):277-83.

Cortisol levels were measured before and after administration of naloxone-HCl in patients with affective disorder (n = 16) and normal control subjects (n = 8). On two consecutive days, 20 mg of naloxone-HCl or placebo was administered i.v. over 15 minutes in a double-blind crossover design. Blood samples were collected at 30, 15, and l minute(s) both before and after infusion. Cortisol rose from a mean baseline level of 14.8 microgram% to a mean peak level of 23.1 microgram% following the naloxone administration. Significant cortisol increases were found in both the 15- and 30-minute samples during the naloxone session. There were no differences between patient and normal subject samples or between diagnostic groups. A subgroup of manic patients who had responded to naloxone with a reduction of their manic behavior also had an attenuated cortisol response to naloxone. This proved to be an artifact secondary to variability in the cortisol response in these patients.

Quantitative evaluation of opioid withdrawal signs in rats repeatedly treated with morphine and injected with naloxone, in the absence or presence of the antiabstinence agent clonidine.[Pubmed:9523765]

J Pharmacol Toxicol Methods. 1997 Nov;38(3):117-31.

An opioid withdrawal syndrome was induced in rats by repeated morphine administration and final naloxone injection. The withdrawal causes alteration of several physiological signs. The aim of the study was to describe a quantitative opioid abstinence syndrome to validate the methodology by utilizing clonidine, a well-known antiwithdrawal agent, and propose the procedure for the screening of antiabstinence drugs. In particular, rats were treated with saline, morphine, naloxone, morphine and naloxone and four doses of clonidine (0, 0.04, 0.1, and 0.25 mg/kg orally). In rats repeatedly exposed to morphine and then injected with naloxone, signs like excretion of feces and urine, salivation, behavioral jumping and wet dog shakes, rectal temperature, and pain threshold have been observed. Consequently, the objective symptoms observed in morphine plus naloxone-treated animals have been taken as markers of opioid withdrawal. These factors have been quantitatively measured and grouped to form a standardized procedure of opioid abstinence syndrome. In addition, it is possible to observe that the antiabstinence drug clonidine exerted effects on modified physiological signs appearing in morphine-dependent rats treated with naloxone, like fecal excretion, levels of rectal temperature, latency times, salivation as well as jumping behavior. The effects exerted by clonidine in this procedure and in other methods are compared and appear to be similar. In addition, comparative observations referring to both the previous methods and the present procedure related to the type of signs studied, the modality of evaluation, and suppressive activity exerted by the antiwithdrawal agent, clonidine, are performed: the greater accuracy of the proposed method becomes apparent. Thus, this experimental model, validated by the antiabstinence agent clonidine, is proposed as a useful screen for drugs affecting opioid withdrawal syndrome.

Naloxone activation of mu-opioid receptors mutated at a histidine residue lining the opioid binding cavity.[Pubmed:9415708]

Mol Pharmacol. 1997 Dec;52(6):983-92.

The mu-opioid receptor is the principal site of action in the brain by which morphine, other opiate drugs of abuse, and endogenous opioid peptides effect analgesia and alter mood. A member of the seven-transmembrane domain (TM) G protein-coupled receptor (GPCR) superfamily, the mu-opioid receptor modulates ion channels and second messenger effectors in an opioid agonist-dependent fashion that is reversible by the classic opiate antagonist naloxone. Mutation of a histidine residue (His297) in TM 6 afforded agonist-like G protein-coupled signal transduction mediated by naloxone and other alkaloid antagonists and enhanced the intrinsic activity of documented alkaloid partial agonists, including buprenorphine. The intrinsic activities of all opioid peptide agonists and antagonists tested were not altered at the His297 mutant receptors. Consistent with a role for the TM 6 histidine in maintaining high affinity binding sites for opioid agonists and antagonists, opioid ligand-dependent protection of this residue from a histidine-specific alkylating agent indicated that the His297 side chain is positioned in or very near the binding cavity. The TM 6 His297 mutants identify a discrete region of the receptor critical for determining whether a specific drug pharmacophore triggers receptor activation. Because many GPCRs possess a similarly positioned TM histidine residue, our findings with the mu-opioid receptor may extend to these receptors and potentially serve as a model for rational design of therapeutic GPCR partial agonists and antagonists.