Editing Fentanyl (section)

=== Mechanism of action ===
{| class="wikitable" style = "float: right; clear: right; margin-left:15px; text-align:center"
|+Fentanyl at opioid receptors<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 }}</ref>
! colspan="3" |[[Binding affinity|Affinities]], {{abbrlink|K<sub>i</sub>|Inhibitor constant}}
!Ratio
|-
!{{abbrlink|MOR|μ-opioid receptor}}
!{{abbrlink|DOR|δ-opioid receptor}}
!{{abbrlink|KOR|κ-opioid receptor}}
!MOR:DOR:KOR
|-
|0.39 nM
|>1,000 nM
|255 nM
|1:>2564:654
|}
Fentanyl, like other opioids, acts on opioid receptors. These receptors are [[G protein-coupled receptor|G-protein-coupled receptors]], which contain seven transmembrane portions, intracellular loops, extracellular loops, intracellular C-terminus, and extracellular N-terminus.<ref name="Hemmings_2018" /> The extracellular N-terminus is important in differentiating different types of binding substrates.<ref name="Hemmings_2018" /> When fentanyl binds, downstream signaling leads to inhibitory effects, such as decreased [[Cyclic adenosine monophosphate|cAMP]] production, decreased calcium ion influx, and increased potassium efflux.<ref name="Hemmings_2018" /> This inhibits the ascending pathways in the central nervous system to increase pain threshold by changing the perception of pain; this is mediated by decreasing propagation of [[Nociception|nociceptive]] signals, resulting in analgesic effects.<ref name="Suzuki17" /><ref>{{cite web|url=https://www.drugbank.ca/drugs/DB00813|title=Fentanyl|website=www.drugbank.ca|access-date=18 January 2019|archive-date=11 July 2017|archive-url=https://web.archive.org/web/20170711073330/https://www.drugbank.ca/drugs/DB00813|url-status=live}}</ref>{{unreliable medical source|date=July 2024}}

As a μ-receptor agonist, fentanyl binds 50 to 100 times more potently than morphine.<ref name="Suzuki17">{{cite journal | vauthors = Suzuki J, El-Haddad S | title = A review: Fentanyl and non-pharmaceutical fentanyls | journal = Drug and Alcohol Dependence | volume = 171 | pages = 107–116 | date = February 2017 | pmid = 28068563 | doi = 10.1016/j.drugalcdep.2016.11.033 }}</ref> It can also bind to the delta and kappa opioid receptors but with a lower affinity. It has high lipid solubility, allowing it to penetrate more easily the [[central nervous system]].<ref name="Yaksh_2011" /><ref name="Mayes_2006">{{cite journal | vauthors = Mayes S, Ferrone M | title = Fentanyl HCl patient-controlled iontophoretic transdermal system for the management of acute postoperative pain | journal = The Annals of Pharmacotherapy | volume = 40 | issue = 12 | pages = 2178–2186 | date = December 2006 | pmid = 17164395 | doi = 10.1345/aph.1H135 | url = http://www.medscape.com/viewarticle/549359_3 | url-status = live | access-date = 17 December 2010 | s2cid = 24454875 | archive-url = https://web.archive.org/web/20121001210131/http://www.medscape.com/viewarticle/549359_3 | archive-date = 1 October 2012 }}</ref> It attenuates "second pain" with primary effects on slow-conducting, unmyelinated C-fibers and is less effective on neuropathic pain and "first pain" signals through small, myelinated A-fibers.<ref name="Hemmings_2018" />

Fentanyl can produce the following clinical effects strongly, through μ-receptor agonism:<ref name = "Butterworth_2018">{{cite book | vauthors = Butterworth IV JV, Wasnick JD, MacKey DC |date = 21 August 2018 |title=Morgan & Mikhail's Clinical Anesthesiology |edition=6th |isbn=978-1-259-83442-4 |place=New York | publisher = McGraw-Hill Education |oclc=1039081701}}</ref>
* Supraspinal analgesia (μ<sub>1</sub>)
* [[Hypoventilation|Respiratory depression]] (μ<sub>2</sub>)
* Physical dependence
* [[Hypertonia|Muscle rigidity]]

It also produces sedation and spinal analgesia through Κ-receptor agonism.<ref name = "Butterworth_2018" />