Editing Heroin (section)

==Pharmacology==
[[File:Heroin black tar.jpg|thumb|[[Black tar heroin]] ]]
When taken orally, heroin undergoes extensive [[first-pass metabolism]] via [[acetylation|deacetylation]], making it a [[prodrug]] for the systemic delivery of morphine.<ref name="Sawynok 1986">{{cite journal | vauthors = Sawynok J | title = The therapeutic use of heroin: a review of the pharmacological literature | journal = Canadian Journal of Physiology and Pharmacology | volume = 64 | issue = 1 | pages = 1–6 | date = January 1986 | pmid = 2420426 | doi = 10.1139/y86-001 }}</ref> When the drug is injected, however, it avoids this first-pass effect, very rapidly crossing the [[blood–brain barrier]] because of the presence of the acetyl groups, which render it much more [[lipophilicity|fat soluble]] than morphine itself.<ref name="Klous 2005">{{cite journal | vauthors = Klous MG, Van den Brink W, Van Ree JM, Beijnen JH | title = Development of pharmaceutical heroin preparations for medical co-prescription to opioid dependent patients | journal = Drug and Alcohol Dependence | volume = 80 | issue = 3 | pages = 283–95 | date = December 2005 | pmid = 15916865 | doi = 10.1016/j.drugalcdep.2005.04.008 }}</ref> Once in the brain, it then is deacetylated variously into the inactive 3-monoacetylmorphine and the active [[6-monoacetylmorphine]] (6-MAM), and then to morphine, which bind to [[μ-opioid receptor]]s, resulting in the drug's euphoric, [[analgesia|analgesic]] (pain relief), and [[anxiolytic]] (anti-anxiety) effects; heroin itself exhibits relatively low affinity for the μ receptor.<ref>{{cite journal | vauthors = Inturrisi CE, Schultz M, Shin S, Umans JG, Angel L, Simon EJ | title = Evidence from opiate binding studies that heroin acts through its metabolites | journal = Life Sciences | volume = 33 | issue = Suppl 1 | pages = 773–6 | year = 1983 | pmid = 6319928 | doi = 10.1016/0024-3205(83)90616-1 }}</ref> Analgesia follows from the activation of the μ receptor [[G-protein coupled receptor]], which indirectly hyperpolarizes the neuron, reducing the release of [[nociception|nociceptive]] neurotransmitters, and hence, causes analgesia and increased pain tolerance.<ref>{{cite book | vauthors = Hitchings A, Lonsdale D, Burrage D, Baker E |title=Top 100 drugs: clinical pharmacology and practical prescribing |date=2014 |publisher=Churchill Livingstone |isbn=978-0-7020-5516-4}}</ref>

Unlike [[hydromorphone]] and [[oxymorphone]], however, administered intravenously, heroin creates a larger histamine release, similar to morphine, resulting in the feeling of a greater subjective "body high" to some, but also instances of [[Itch|pruritus]] (itching) when they first start using.<ref>{{cite web|url=http://grande.nal.usda.gov/ibids/index.php?mode2=detail&origin=ibids_references&therow=35525|title=Histamine release by morphine and diamorphine in man | archive-url=https://web.archive.org/web/20100812062454/http://grande.nal.usda.gov/ibids/index.php?mode2=detail&origin=ibids_references&therow=35525 | archive-date=12 August 2010 }}</ref><ref name="pmid14746612">{{cite journal | vauthors = Del Giudice P | title = Cutaneous complications of intravenous drug abuse | journal = The British Journal of Dermatology | volume = 150 | issue = 1 | pages = 1–10 | date = January 2004 | pmid = 14746612 | doi = 10.1111/j.1365-2133.2004.05607.x | s2cid = 32380001 | url = http://bcbsma.medscape.com/viewarticle/468419_4 |archive-url=https://archive.today/20121123175249/http://bcbsma.medscape.com/viewarticle/468419_4|archive-date=23 November 2012|url-status=live }}</ref>

Normally, [[GABA]], which is released from inhibitory neurones, inhibits the release of dopamine. Opiates, like heroin and morphine, decrease the inhibitory activity of such neurones. This causes increased release of dopamine in the brain which is the reason for euphoric and rewarding effects of heroin.<ref>{{cite book | vauthors = Papich MG |title=Saunders Handbook of Veterinary Drugs |date=2016 |publisher=W.B. Saunders |isbn=978-0-323-24485-5 |pages=183–184 |doi=10.1016/B978-0-323-24485-5.00175-3|chapter=Codeine|edition=Fourth }}</ref>

Both morphine and 6-MAM are [[μ-opioid receptor|μ-opioid]] [[agonist]]s that bind to receptors present throughout the brain, [[spinal cord]], and [[gut (zoology)|gut]] of all [[mammal]]s. The μ-opioid receptor also binds endogenous [[opioid peptide]]s such as [[β-endorphin]], [[leu-enkephalin]], and [[met-enkephalin]]. Repeated use of heroin results in a number of physiological changes, including an increase in the production of μ-opioid receptors (upregulation).<ref>{{cite journal | vauthors = Hammers A, Asselin MC, Hinz R, Kitchen I, Brooks DJ, Duncan JS, Koepp MJ | title = Upregulation of opioid receptor binding following spontaneous epileptic seizures | journal = Brain | volume = 130 | issue = Pt 4 | pages = 1009–16 | date = April 2007 | pmid = 17301080 | doi = 10.1093/brain/awm012 | doi-access = free }}</ref> These physiological alterations lead to tolerance and dependence, so that stopping heroin use results in uncomfortable symptoms including pain, anxiety, muscle spasms, and insomnia called the opioid [[drug withdrawal|withdrawal]] syndrome. Depending on usage it has an onset 4–24&nbsp;hours after the last dose of heroin. Morphine also binds to [[δ-opioid receptor|δ]]- and [[κ-opioid receptor]]s.

There is also evidence that 6-MAM binds to a subtype of μ-opioid receptors that are also activated by the morphine metabolite morphine-6β-glucuronide but not morphine itself.<ref>{{cite journal | vauthors = Brown GP, Yang K, King MA, Rossi GC, Leventhal L, Chang A, Pasternak GW | title = 3-Methoxynaltrexone, a selective heroin/morphine-6beta-glucuronide antagonist | journal = FEBS Letters | volume = 412 | issue = 1 | pages = 35–8 | date = July 1997 | pmid = 9257684 | doi = 10.1016/S0014-5793(97)00710-2 | s2cid = 45475657 | doi-access = free | bibcode = 1997FEBSL.412...35B }}</ref> The third subtype of third opioid type is the mu-3 receptor, which may be a commonality to other six-position monoesters of morphine. The contribution of these receptors to the overall pharmacology of heroin remains unknown.

A subclass of morphine derivatives, namely the 3,6 esters of morphine, with similar effects and uses, includes the clinically used strong analgesics [[nicomorphine]] (Vilan), and [[dipropanoylmorphine]]; there is also the latter's [[dihydromorphine]] analogue, [[diacetyldihydromorphine]] (Paralaudin). Two other 3,6 diesters of morphine invented in 1874–75 along with diamorphine, [[dibenzoylmorphine]] and [[acetylpropionylmorphine]], were made as substitutes after it was outlawed in 1925 and, therefore, sold as the first "[[designer drugs]]" until they were outlawed by the [[League of Nations]] in 1930.