Editing Morphine (section)

=== Pharmacodynamics ===
{| class="wikitable floatright" style="text-align: center;"
|+ Morphine at opioid receptors
|-
! rowspan="2" | Compound || colspan="3" | [[Binding affinity|Affinities]] ({{abbrlink|K<sub>i</sub>|Inhibitor constant}}) || Ratio || rowspan="2" | Ref
|-
! {{abbrlink|MOR|μ-Opioid receptor}} !! {{abbrlink|DOR|δ-Opioid receptor}} !! {{abbrlink|KOR|κ-Opioid receptor}} !! MOR:DOR:KOR
|-
| Morphine || 1.8 nM || 90 nM || 317 nM || 1:50:176 || <ref name="CorbettPaterson1993">{{cite book| vauthors = Corbett AD, Paterson SJ, Kosterlitz HW |chapter=Selectivity of Ligands for Opioid Receptors |title=Opioids |volume=104 / 1|year=1993|pages=645–679|issn=0171-2004|doi=10.1007/978-3-642-77460-7_26|series=Handbook of Experimental Pharmacology | publisher = Springer | location = Berlin, Heidelberg|isbn=978-3-642-77462-1}}</ref>
|-
| (−)-Morphine || 1.24 nM || 145 nM || 23.4 nM || 1:117:19 || <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 = 1263–70 | date = September 1995 | doi = 10.1016/S0022-3565(25)10630-7 | pmid = 7562497 }}</ref>
|-
| (+)-Morphine || >10 μM || >100 μM || >300 μM || {{abbr|ND|No data}} || <ref name="pmid7562497" />
|}

{| class="wikitable floatright"
|+ <br />Equianalgesic doses<ref name="King2010">{{cite book| vauthors = King TL, Brucker MC |title=Pharmacology for Women's Health|url=https://books.google.com/books?id=o_rHHCsIpckC&pg=PA332|date=25 October 2010|publisher=Jones & Bartlett Publishers|isbn=978-1-4496-1073-9|pages=332–}}</ref><ref name="ChestnutWong2014">{{cite book | vauthors = Flood P, Aleshi P | chapter = Postoperative and chronic pain: systemic and regional pain techniques | veditors = Chestnut DH, Wong CA, Tsen KC, Ngan Kee WD, Beilin Y, Mhyre J |title=Chestnut's Obstetric Anesthesia: Principles and Practice E-Book|chapter-url=https://books.google.com/books?id=FMU0AwAAQBAJ&pg=PA611|date=28 February 2014|publisher=Elsevier Health Sciences|isbn=978-0-323-11374-8|pages=611–}}</ref><ref name="Tiziani2013">{{cite book| vauthors = Tiziani AP |title=Havard's Nursing Guide to Drugs|url=https://books.google.com/books?id=XpzQAgAAQBAJ&pg=PA933|date=1 June 2013|publisher=Elsevier Health Sciences|isbn=978-0-7295-8162-2|pages=933–}}</ref>
|-
! Compound !! [[Route of administration|Route]] !! [[Dose (biochemistry)|Dose]]
|-
| [[Codeine]] || {{abbr|PO|Oral administration}} || 200&nbsp;mg
|-
| [[Hydrocodone]] || {{abbr|PO|Oral administration}} || 30&nbsp;mg
|-
| [[Hydromorphone]] || {{abbr|PO|Oral administration}} || 7.5&nbsp;mg
|-
| [[Hydromorphone]] || {{abbr|IV|Intravenous administration}} || 2&nbsp;mg
|-
| Morphine || {{abbr|PO|Oral administration}} || 30&nbsp;mg
|-
| Morphine || {{abbr|IV|Intravenous administration}} || 10&nbsp;mg
|-
| [[Oxycodone]] || {{abbr|PO|Oral administration}} || 20&nbsp;mg
|-
| [[Oxycodone]] || {{abbr|IV|Intravenous administration}} || 20&nbsp;mg
|-
| [[Oxymorphone]] || {{abbr|PO|Oral administration}} || 10&nbsp;mg
|-
| [[Oxymorphone]] || {{abbr|IV|Intravenous administration}} || 1&nbsp;mg
|-
| [[Buprenorphine]] || {{abbr|IV|Intravenous administration}} || 0,3&nbsp;mg
|}

Due to its long history and established use as a pain medication, this compound has become the benchmark to which all other opioids are compared.<ref>{{cite book | vauthors = Ogura T, Egan TD |title = Pharmacology and physiology for anesthesia: foundations and clinical application |date = 2013 |publisher = Elsevier/Saunders |location = Philadelphia, PA |isbn = 978-1-4377-1679-5 |doi=10.1016/B978-1-4377-1679-5.00015-6 |chapter = Chapter 15 – Opioid Agonists and Antagonists }}</ref> It interacts predominantly with the μ–δ-opioid (Mu-Delta) [[GPCR oligomer|receptor heteromer]].<ref>{{cite journal | vauthors = Yekkirala AS, Kalyuzhny AE, Portoghese PS | title = Standard opioid agonists activate heteromeric opioid receptors: evidence for morphine and [d-Ala(2)-MePhe(4)-Glyol(5)]enkephalin as selective μ-δ agonists | journal = ACS Chemical Neuroscience | volume = 1 | issue = 2 | pages = 146–54 | date = February 2010 | pmid = 22816017 | pmc = 3398540 | doi = 10.1021/cn9000236 }}</ref><ref>{{cite journal | vauthors = Yekkirala AS, Banks ML, Lunzer MM, Negus SS, Rice KC, Portoghese PS | title = Clinically employed opioid analgesics produce antinociception via μ-δ opioid receptor heteromers in Rhesus monkeys | journal = ACS Chemical Neuroscience | volume = 3 | issue = 9 | pages = 720–7 | date = September 2012 | pmid = 23019498 | pmc = 3447399 | doi = 10.1021/cn300049m }}</ref> The μ-binding sites are discretely distributed in the [[human brain]], with high densities in the posterior [[amygdala]], [[hypothalamus]], [[thalamus]], [[nucleus caudatus]], [[putamen]], and certain cortical areas. They are also found on the [[chemical synapse|terminal axons]] of primary afferents within laminae [[posteromarginal nucleus|I]] and II ([[substantia gelatinosa of Rolando|substantia gelatinosa]]) of the spinal cord and in the spinal nucleus of the [[trigeminal nerve]].<ref name="rxlist.com">{{cite web |url = http://www.rxlist.com/cgi/generic/ms_cp.htm |title = MS-Contin (Morphine Sulfate Controlled-Release) Drug Information: Clinical Pharmacology |website = Prescribing Information |publisher = RxList |url-status = dead |archive-url = https://web.archive.org/web/20070515141904/http://www.rxlist.com/cgi/generic/ms_cp.htm |archive-date = 15 May 2007 }}</ref>

Morphine is a [[phenanthrene]] [[opioid receptor]] [[receptor agonist|agonist]]&nbsp;– its main effect is binding to and activating the [[μ-opioid receptor]] (MOR) in the [[central nervous system]]. Its [[intrinsic activity]] at the MOR is heavily dependent on the [[assay]] and tissue being tested; in some situations it is a [[full agonist]] while in others it can be a [[partial agonist]] or even [[receptor antagonist|antagonist]].<ref name="pmid23646826">{{cite journal | vauthors = Kelly E | title = Efficacy and ligand bias at the μ-opioid receptor | journal = British Journal of Pharmacology | volume = 169 | issue = 7 | pages = 1430–46 | date = August 2013 | pmid = 23646826 | pmc = 3724102 | doi = 10.1111/bph.12222 }}</ref> In clinical settings, morphine exerts its principal pharmacological effect on the central nervous system and [[human gastrointestinal tract|gastrointestinal tract]]. Its primary actions of therapeutic value are analgesia and sedation. Activation of the MOR is associated with analgesia, sedation, [[euphoria (emotion)|euphoria]], physical [[chemical dependency|dependence]], and [[respiratory depression]]. Morphine is also a [[κ-opioid receptor]] (KOR) and [[δ-opioid receptor]] (DOR) agonist. Activation of the KOR is associated with spinal analgesia, [[miosis]] (pinpoint pupils), and [[psychotomimetic]] effects. The DOR is thought to play a role in analgesia.<ref name="rxlist.com" />{{Failed verification|date=August 2023}} Although morphine does not bind to the [[sigma receptor|σ receptor]], it has been shown that σ receptor agonists, such as [[pentazocine|(+)-pentazocine]], inhibit morphine analgesia, and σ receptor antagonists enhance morphine analgesia,<ref>{{cite journal | vauthors = Chien CC, Pasternak GW | title = Sigma antagonists potentiate opioid analgesia in rats | journal = Neuroscience Letters | volume = 190 | issue = 2 | pages = 137–9 | date = May 1995 | pmid = 7644123 | doi = 10.1016/0304-3940(95)11504-P | s2cid = 10033780 | doi-access = free }}</ref> suggesting downstream involvement of the σ receptor in the actions of morphine.

The effects of morphine can be countered with [[opioid receptor antagonist]]s such as [[naloxone]] and [[naltrexone]]; the development of tolerance to morphine may be inhibited by [[NMDA receptor antagonist]]s such as [[ketamine]], [[dextromethorphan]], and [[memantine]].<ref name="pmid8747752">{{cite journal | vauthors = Herman BH, Vocci F, Bridge P | title = The effects of NMDA receptor antagonists and nitric oxide synthase inhibitors on opioid tolerance and withdrawal. Medication development issues for opiate addiction | journal = Neuropsychopharmacology | volume = 13 | issue = 4 | pages = 269–293 | date = December 1995 | pmid = 8747752 | doi = 10.1016/0893-133X(95)00140-9 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Popik P, Kozela E, Danysz W | title = Clinically available NMDA receptor antagonists memantine and dextromethorphan reverse existing tolerance to the antinociceptive effects of morphine in mice | journal = Naunyn-Schmiedeberg's Archives of Pharmacology | volume = 361 | issue = 4 | pages = 425–432 | date = April 2000 | pmid = 10763858 | doi = 10.1007/s002109900205 | s2cid = 18200635 }}</ref> The rotation of morphine with chemically dissimilar opioids in the long-term treatment of pain will slow down the growth of tolerance in the longer run, particularly agents known to have significantly incomplete cross-tolerance with morphine such as [[levorphanol]], [[ketobemidone]], [[piritramide]], and [[methadone]] and its derivatives; all of these drugs also have NMDA antagonist properties. It is believed that the strong opioid with the most incomplete cross-tolerance with morphine is either methadone<ref>{{cite journal | vauthors = Crews JC, Sweeney NJ, Denson DD | title = Clinical efficacy of methadone in patients refractory to other mu-opioid receptor agonist analgesics for management of terminal cancer pain. Case presentations and discussion of incomplete cross-tolerance among opioid agonist analgesics | journal = Cancer | volume = 72 | issue = 7 | pages = 2266–2272 | date = October 1993 | pmid = 7690683 | doi = 10.1002/1097-0142(19931001)72:7<2266::AID-CNCR2820720734>3.0.CO;2-P | s2cid = 19669811 }}</ref> or [[dextromoramide]].{{Citation needed|date=October 2021}}
[[File:Morphine_Ampoule_For_Veterinary_Use.jpg|thumb|Morphine [[hydrochloride]] ampoule for [[Veterinary medicine|veterinary use]]]]

==== Analgesia creation ====
Morphine creates analgesia through the activation of a specific group of neurons in the [[rostral ventromedial medulla]], called the "morphine ensemble."<ref name="j866">{{cite journal | vauthors = Fatt MP, Zhang MD, Kupari J, Altınkök M, Yang Y, Hu Y, Svenningsson P, Ernfors P |date=30 August 2024 |title=Morphine-responsive neurons that regulate mechanical antinociception |journal=Science |volume=385 |issue=6712 |pages=eado6593 |doi=10.1126/science.ado6593 |pmid=39208104 |issn=0036-8075|pmc=7616448 |bibcode=2024Sci...385o6593F }}</ref> This ensemble includes glutamatergic neurons that project to the spinal cord, known as RVM<sup>BDNF</sup> neurons. These neurons connect to inhibitory neurons in the spinal cord, called SC<sup>Gal</sup> neurons, which release the neurotransmitter GABA and the neuropeptide [[galanin]]. The inhibition of SC<sup>Gal</sup> neurons is crucial for morphine's pain-relieving effects. Additionally, the neurotrophic factor [[Brain-derived neurotrophic factor|BDNF]], produced within the RVM<sup>BDNF</sup> neurons, is required for morphine's action. Increasing BDNF levels enhances morphine's analgesic effects, even at lower doses.<ref name="v878">{{cite journal | vauthors = De Preter CC, Heinricher MM |date=30 August 2024 |title=Opioid circuit opens path to pain relief |journal=Science |volume=385 |issue=6712 |pages=932–933 |doi=10.1126/science.adr5900 |pmid=39208119 |bibcode=2024Sci...385..932D |issn=0036-8075}}</ref><ref name="j866" />

==== Gene expression ====
Studies have shown that morphine can alter the expression of several [[genes]]. A single injection of morphine has been shown to alter the expression of two major groups of genes, for proteins involved in [[mitochondria]]l respiration and for [[cytoskeleton]]-related proteins.<ref>{{cite journal | vauthors = Loguinov AV, Anderson LM, Crosby GJ, Yukhananov RY | title = Gene expression following acute morphine administration | journal = Physiological Genomics | volume = 6 | issue = 3 | pages = 169–81 | date = August 2001 | pmid = 11526201 | doi = 10.1152/physiolgenomics.2001.6.3.169 | s2cid = 9296949 }}</ref>

==== Effects on the immune system ====
Morphine has long been known to act on receptors expressed in cells of the [[central nervous system]] resulting in pain relief and [[analgesia]]. In the 1970s and '80s, evidence suggesting that people addicted to opioids show an increased risk of infection (such as increased [[pneumonia]], [[tuberculosis]], and [[HIV/AIDS]]) led scientists to believe that morphine may also affect the [[immune system]]. This possibility increased interest in the effect of chronic morphine use on the immune system.<ref>{{cite journal | vauthors = Sacerdote P | title = Opioids and the immune system | journal = Palliative Medicine | volume = 20 | pages = s9-15 | date = 2006 | issue = Suppl 1 | doi = 10.1191/0269216306pm1124oa | pmid = 16764216 | s2cid = 39489581 }}</ref>

The first step in determining that morphine may affect the immune system was to establish that the opiate receptors known to be expressed on cells of the central nervous system are also expressed on cells of the immune system. One study successfully showed that [[dendritic cells]], part of the innate immune system, display opiate receptors. Dendritic cells are responsible for producing [[cytokine]]s, which are the tools for communication in the immune system. This same study showed that dendritic cells chronically treated with morphine during their differentiation produce more [[interleukin-12]] (IL-12), a cytokine responsible for promoting the proliferation, growth, and differentiation of T-cells (another cell of the adaptive immune system) and less [[interleukin-10]] (IL-10), a cytokine responsible for promoting a B-cell immune response (B cells produce antibodies to fight off infection).<ref name="messmer 2006">{{cite journal | vauthors = Messmer D, Hatsukari I, Hitosugi N, Schmidt-Wolf IG, Singhal PC | title = Morphine reciprocally regulates IL-10 and IL-12 production by monocyte-derived human dendritic cells and enhances T cell activation | journal = Molecular Medicine | volume = 12 | issue = 11–12 | pages = 284–90 | year = 2006 | pmid = 17380193 | pmc = 1829197 | doi = 10.2119/2006-00043.Messmer }}</ref>

This regulation of cytokines appears to occur via the [[p38 MAPK pathway|p38 MAPKs (mitogen-activated protein kinase)-dependent pathway]]. Usually, the p38 within the dendritic cell expresses [[TLR 4]] (toll-like receptor 4), which is activated through the ligand LPS ([[lipopolysaccharide]]). This causes the p38 MAPK to be [[phosphorylation|phosphorylated]]. This phosphorylation activates the [[p38 mitogen-activated protein kinases|p38 MAPK]] to begin producing IL-10 and IL-12. When the dendritic cells are chronically exposed to morphine during their differentiation process and then treated with LPS, the production of cytokines is different. Once treated with morphine, the p38 MAPK does not produce IL-10, instead favoring the production of IL-12. The exact mechanism through which the production of one cytokine is increased in favor over another is not known. Most likely, the morphine causes increased phosphorylation of the p38 MAPK. Transcriptional level interactions between IL-10 and IL-12 may further increase the production of IL-12 once IL-10 is not being produced. This increased production of IL-12 causes increased T-cell immune response.

Further studies on the effects of morphine on the immune system have shown that morphine influences the production of [[neutrophils]] and other [[cytokines]]. Since cytokines are produced as part of the immediate immunological response ([[inflammation]]), it has been suggested that they may also influence pain. In this way, cytokines may be a logical target for analgesic development. Recently, one study has used an animal model (hind-paw incision) to observe the effects of morphine administration on the acute immunological response. Following the hind-paw incision, pain thresholds and cytokine production were measured. Normally, cytokine production in and around the wounded area increases to fight [[infection]] and control healing (and, possibly, to control pain), but pre-incisional morphine administration (0.1&nbsp;mg/kg to 10.0&nbsp;mg/kg) reduced the number of cytokines found around the wound in a dose-dependent manner. The authors suggest that morphine administration in the acute post-injury period may reduce resistance to infection and may impair the healing of the wound.<ref name="pmid17908329">{{cite journal | vauthors = Clark JD, Shi X, Li X, Qiao Y, Liang D, Angst MS, Yeomans DC | title = Morphine reduces local cytokine expression and neutrophil infiltration after incision | journal = Molecular Pain | volume = 3 | pages = 1744-8069-3-28 | date = October 2007 | pmid = 17908329 | pmc = 2096620 | doi = 10.1186/1744-8069-3-28 | doi-access = free }}</ref>