Editing Naloxone (section)

===Pharmacodynamics===
{| class="wikitable floatright" style="text-align: center;"
|+ Naloxone at opioid receptors
|-
! rowspan="2" | Compound || colspan="3" |[[Binding affinity|Affinities]] ({{abbrlink|K<sub>i</sub>|Inhibitor constant}}) || Ratios || rowspan="2" | Refs
|-
!{{abbrlink|MOR|μ-Opioid receptor}}!!{{abbrlink|DOR|δ-Opioid receptor}}!!{{abbrlink|KOR|κ-Opioid receptor}}!! MOR:DOR:KOR
|-
| Naloxone || 1.1 nM<br />1.4 nM || 16 nM<br />67.5 nM || 12 nM<br />2.5 nM || 1:15:11<br />1:48:1.8 ||<ref name="pmid2986989">{{cite journal | vauthors = Tam SW | title = (+)-[3H]SKF 10,047, (+)-[3H]ethylketocyclazocine, mu, kappa, delta and phencyclidine binding sites in guinea pig brain membranes | journal = European Journal of Pharmacology | volume = 109 | issue = 1 | pages = 33–41 | date = February 1985 | pmid = 2986989 | doi = 10.1016/0014-2999(85)90536-9 }}</ref><br /><ref name="pmid9686407">{{cite journal | vauthors = Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, Schwartz RW, Haggart D, O'Brien A, White A, Kennedy JM, Craymer K, Farrington L, Auh JS | title = Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications | journal = NIDA Research Monograph | volume = 178 | pages = 440–466 | date = March 1998 | pmid = 9686407 }}</ref><ref name="pmid31376930">{{cite journal | vauthors = Clark SD, Abi-Dargham A | title = The Role of Dynorphin and the Kappa Opioid Receptor in the Symptomatology of Schizophrenia: A Review of the Evidence | journal = Biological Psychiatry | volume = 86 | issue = 7 | pages = 502–511 | date = October 2019 | pmid = 31376930 | doi = 10.1016/j.biopsych.2019.05.012 | s2cid = 162168648 | doi-access = free | title-link = doi }}</ref>
|-
| (−)-Naloxone || 0.559 nM<br />0.93 nM || 36.5 nM<br />17 nM || 4.91 nM<br />2.3 nM || 1:65:9<br />1:18:2 ||<ref name="pmid7562497">{{cite journal | vauthors = Codd EE, Shank RP, Schupsky JJ, Raffa RB | title = Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 274 | issue = 3 | pages = 1263–1270 | date = September 1995 | doi = 10.1016/S0022-3565(25)10630-7 | pmid = 7562497 | url = http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=7562497 | access-date = 13 December 2014 | archive-date = 12 March 2020 | archive-url = https://web.archive.org/web/20200312134749/http://jpet.aspetjournals.org/content/274/3/1263.long | url-status = live }}</ref><br /><ref name="pmid8114680">{{cite journal | vauthors = Raynor K, Kong H, Chen Y, Yasuda K, Yu L, Bell GI, Reisine T | title = Pharmacological characterization of the cloned kappa-, delta-, and mu-opioid receptors | journal = Molecular Pharmacology | volume = 45 | issue = 2 | pages = 330–334 | date = February 1994 | doi = 10.1016/S0026-895X(25)09932-8 | pmid = 8114680 | url = http://molpharm.aspetjournals.org/content/45/2/330.short | access-date = 22 June 2018 | archive-date = 22 June 2018 | archive-url = https://web.archive.org/web/20180622111441/http://molpharm.aspetjournals.org/content/45/2/330.short | url-status = live }}</ref>
|-
| (+)-Naloxone || 3,550 nM<br /> >1,000 nM || 122,000 nM<br /> >1,000 nM || 8,950 nM<br /> >1,000 nM || 1:34:3<br />{{abbr|ND|No data}}||<ref name="pmid7562497"/><br /><ref name="pmid8114680"/>
|}

Naloxone is a [[lipophilic]] compound that acts as a [[non-selective]] and [[competitive antagonist|competitive]] [[opioid receptor antagonist]].<ref name="NHM-Naloxone pharmacology">{{cite book | vauthors = Malenka RC, Nestler EJ, Hyman SE | veditors = Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York | isbn = 9780071481274 | pages = 190–191, 287 | edition = 2nd | quote= Products of this research include the discovery of lipophilic, small-molecule opioid receptor antagonists, such as naloxone and naltrexone, which have been critical tools for investigating the physiology and behavioral actions of opiates.{{nbsp}}... A competitive antagonist of opiate action (naloxone) had been identified in early studies.{{nbsp}}... Opiate antagonists have clinical utility as well. Naloxone, a nonselective antagonist with a relative affinity of μ > δ > κ, is used to treat heroin and other opiate overdoses.}}</ref><ref name="Narcan FDA label">{{cite web | title=Narcan- naloxone hydrochloride spray Narcan- naloxone hydrochloride spray | website=DailyMed | date=7 October 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=724df050-5332-4d0a-9a5f-17bf08a547e1 | access-date=12 May 2020 | archive-date=30 January 2016 | archive-url=https://web.archive.org/web/20160130063652/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=724df050-5332-4d0a-9a5f-17bf08a547e1 | url-status=live }}</ref> The [[eudysmic ratio|pharmacologically active isomer]] of naloxone is (−)-naloxone.<ref name="pmid7562497"/><ref name="Naloxone IUPHAR">{{cite web|title=Naloxone: Summary|url=http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1638|website=IUPHAR/BPS Guide to Pharmacology|publisher=International Union of Basic and Clinical Pharmacology|access-date=15 November 2017|quote=The approved drug naloxone INN-assigned preparation is the (-)-enantiomer.{{nbsp}}... The (+) isomer is inactive at the opioid receptors. Marketed formulations may contain naloxone hydrochloride|archive-date=16 November 2017|archive-url=https://web.archive.org/web/20171116132555/http://www.guidetopharmacology.org/GRAC/LigandDisplayForward?ligandId=1638|url-status=live}}</ref> Naloxone's [[binding affinity]] is highest for the [[μ-opioid receptor]] (MOR), then the [[δ-opioid receptor]] (DOR), and lowest for the [[κ-opioid receptor]] (KOR);<ref name="NHM-Naloxone pharmacology"/> naloxone has negligible affinity for the [[nociceptin receptor]].<ref name="Opioid receptor family – IUPHAR">{{cite web|title=Opioid receptors: Introduction|url=http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=50|website=IUPHAR/BPS Guide to Pharmacology|publisher=International Union of Basic and Clinical Pharmacology|access-date=15 November 2017|quote=The opioid antagonist, naloxone, which binds to μ, δ and κ receptors (with differing affinities), does not have significant affinity for the ORL1/LC132 receptor. These studies indicate that, from a pharmacological perspective, there are two major branches in the opioid peptide-N/OFQ receptor family: the main branch comprising the μ, δ, and κ receptors, where naloxone acts as an antagonist; and a second branch with the receptor for N/OFQ, which has negligible affinity for naloxone.|archive-date=21 October 2017|archive-url=https://web.archive.org/web/20171021111918/http://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=50|url-status=live}}</ref>

If naloxone is administered in the absence of concomitant opioid use, no functional pharmacological activity occurs, except the inability of the body to combat pain naturally;<ref name="Naloxone effects on natural analgesia">{{cite journal | vauthors = Schull J, Kaplan H, O'Brien CP |title=Naloxone can alter experimental pain and mood in humans |journal=Physiological Psychology |date=12 June 1981 |volume=9 |issue=3 |pages=245–250 |doi=10.3758/BF03326970 |url=https://link.springer.com/content/pdf/10.3758/BF03326970.pdf |access-date=3 February 2025}}</ref> since pure mu-opioid antagonists like naloxone and [[naltrexone]] block the effects of [[endorphins]].<ref name="Opioid antagonists effects on endorphins">{{cite web |title=Naloxone Frequently Asked Questions |url=https://www.yashodahospitals.com/medicine-faqs/naloxone/ |website=Yashoda Hospitals |access-date=3 February 2025}}</ref><ref name="Naloxone Drug Facts">{{cite web |title=Naloxone Drug Facts |url=https://go.drugbank.com/drugs/DB01183 |website=Go.Drugbank.com |publisher=Drug Bank Online |access-date=3 February 2025}}</ref> In contrast to direct opiate agonists, which elicit opiate withdrawal symptoms when discontinued in opiate-tolerant people, no evidence indicates the development of tolerance or dependence on naloxone. The mechanism of action is not completely understood, but studies suggest it functions to produce withdrawal symptoms by competing for opioid receptors within the brain (a competitive antagonist, not a direct agonist), thereby preventing the action of both [[endogenous]] and [[xenobiotic]] opioids on these receptors without directly producing any effects itself.<ref name="DailyMed">{{cite web|title=Naloxone Hydrochloride injection, solution|url=http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8535cc84-ad4a-4d67-8480-fb5a2e3406f8|publisher=DailyMed |access-date=21 April 2014|url-status=live|archive-url=https://web.archive.org/web/20140422232959/http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=8535cc84-ad4a-4d67-8480-fb5a2e3406f8|archive-date=22 April 2014}}</ref>

A single administration of naloxone at a relatively high dose of 2{{nbsp}}mg by [[intravenous injection]] has been found to produce brain MOR blockade of 80% at 5{{nbsp}}minutes, 47% at 2{{nbsp}}hours, 44% at 4{{nbsp}}hours, and 8% at 8{{nbsp}}hours.<ref name="ColasantiLingford-HughesNutt2013">{{cite book | veditors = Miller PM | title = Biological Research on Addiction | series = Comprehensive Addictive Behaviors and Disorders | volume = 2 | vauthors = Colasanti A, Lingford-Hughes A, Nutt D | chapter = Opioids Neuroimaging | date = 2013 | pages = 675–687 | publisher = Elsevier | doi = 10.1016/B978-0-12-398335-0.00066-2 | isbn = 9780123983350 }}</ref> A low dose (2{{nbsp}}μg/kg) produced brain MOR blockade of 42% at 5{{nbsp}}minutes, 36% at 2{{nbsp}}hours, 33% at 4{{nbsp}}hours, and 10% at 8{{nbsp}}hours.<ref name="ColasantiLingford-HughesNutt2013" /> [[Intranasal administration]] of naloxone via [[nasal spray]] has likewise been found to rapidly occupy brain MORs, with peak occupancy occurring at 20{{nbsp}}minutes, peak occupancies of 67% at a dose of 2{{nbsp}}mg and 85% with 4{{nbsp}}mg, and an estimated half-life of occupancy disappearance of approximately 100{{nbsp}}minutes (1.67{{nbsp}}hours).<ref name="van WaardeAbsalomVisser2020">{{cite book | veditors = Dierckx RA, Otte A, De Vries EF, Van Waarde A, Luiten PG | title = PET and SPECT of Neurobiological Systems | vauthors = Waarde AV, Absalom AR, Visser AK, Dierckx RA | chapter = Positron Emission Tomography (PET) Imaging of Opioid Receptors | date = 30 September 2020 | pages = 749–807 | publisher = Springer International Publishing | doi = 10.1007/978-3-030-53176-8_21 | isbn = 978-3-030-53175-1 | s2cid = 241535315 | url = https://research.rug.nl/en/publications/db18f24c-9750-46f6-932d-634dac427c45 | chapter-url = https://research.rug.nl/en/publications/db18f24c-9750-46f6-932d-634dac427c45 | access-date = 23 January 2023 | archive-date = 9 March 2023 | archive-url = https://web.archive.org/web/20230309063205/https://research.rug.nl/en/publications/positron-emission-tomography-pet-imaging-of-opioid-receptors-2 | url-status = live }}</ref><ref name="pmid30867551">{{cite journal | vauthors = Johansson J, Hirvonen J, Lovró Z, Ekblad L, Kaasinen V, Rajasilta O, Helin S, Tuisku J, Sirén S, Pennanen M, Agrawal A, Crystal R, Vainio PJ, Alho H, Scheinin M | title = Intranasal naloxone rapidly occupies brain mu-opioid receptors in human subjects | journal = Neuropsychopharmacology | volume = 44 | issue = 9 | pages = 1667–1673 | date = August 2019 | pmid = 30867551 | pmc = 6785104 | doi = 10.1038/s41386-019-0368-x }}</ref>