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Mitragynine Attenuates Withdrawal Syndrome in Morphine-Withdrawn Zebrafish

Withdrawalsyndromeconsists of a set of physical and psychologicalsymptomsthatarisewhenpeopleabruptlystopsabusing a substancethattheyhaveabusedbeforeoriftheamount of substancetheyusedtoabstaindecreases.

Theopioidsmostcommonlyinvolved in thewithdrawalsyndrome are: morphine, meperidine, codeine, oxycodone, tramadol, hydromorphone and heroin, whetherthey are usedtherapeutically (forexample, in thetreatment of chronicpain) orifthey are used as substances of abuse (heroin)

Allthesesubstanceshave in commonthattheyactonopioidreceptors; Many of them are used in medicine, mainlybecause of theirpotentanalgesiceffect, buttheyhavea greatpotentialfor abuse duetotheirpsychoactiveproperties.

Ourbodyisalways in search of homeostasis. Thus, whenitreceives in a verycontinuouswaythesamesubstance, a series of mechanismsthataimtoreturntothepreviousstate are triggered. Thatis, keepworkingwithouttheconsumption of thedrugaffectsit.

Therefore, ifthesubstanceis removed, the homeostasis reachedisbroken and theunpleasantsymptoms of thewithdrawalsyndromeappear.

Clinicalmanifestations

Theclinicalpictureis similar withallopioids, and includesthreephases:

Initialphase: thereisthepresence of rhinorrhea, epiphoraorlacrimation, yawning, anxiety and sweating; Generally, itappearswithin 8-12 hoursafterthelastdose of theopioid.

Intermediatephase: occurswhenthewithdrawalsyndromereachesitsgreatestintensity. Itischaracterizedbymydriasis, piloerection, myalgias, arthralgias, muscular contractures, bonepain, diaphoresis, tachycardia, hypertension, tremor, irritability, motor agitation, anorexia and insomnia.

Late phase: paresthesias, fever, colicky abdominal pain, nausea, vomits, diarrhea and hyperglycemia, and spontaneousorgasmsorejaculationsmayappear.

Thedesiretoavoid and escape theaversivesymptoms of abstinence can lead undesirablytothesearchforopiates, which causes a relapse. Therefore, a majorgoal in thetreatment of addictionisto relieve theseverity of opioidwithdrawalsymptoms.

A series of experimentswascarriedouttoinvestigatetheeffect of mitragynineonanxietybehavior, cortisol level and theexpression of genes relatedtothe stress pathway in zebrafish in phase of morphinewithdrawal

Theresearchersdecipheredthezebrafishgenome, a "modelorganism" commonlyused in laboratoriestostudy human diseases.

Thisgenomeisthelargestdeciphered so farwith, 26,000 genes encoded, and wassequenced so accuratelythatwe can actuallymakedirectcomparisonsbetween human genes and zebrafish genes. Its DNA isvery similar tothat of men, 70% of human genes have a homolog in zebrafish and in the genes associatedwith human pathologies, theproportionrisesto 84%

Theirembryos, beingtransparent, makeitpossibletoseetheeffects of thedrugsinsidetheirorgans. Thereis no problemwhenit comes todyeingtheirviscera and theirrapiddevelopmentgivethepossibility of studyingnumerousdiseasesinduced in a samegeneration and identifythe causes.

Cortisol is a hormone producedbyinterrenalcellsin fish (in mammalsitisproduced in the adrenal glands), whichunder normal conditionsplays a veryimportant role in processes of metabolism, growth, energyregulation and hydromineral balance. Under stress conditions, cortisol ispart of thebody'sprimaryresponse, so itisused as one of themostimportantphysiological stress markers in fish. Under normal conditions, vertebratespresentdailyrhythms of cortisol secretion, withproductionmaximums at thebeginning of theactivityphase.

A majorobstacle in thetreatment of drugaddictionistheseverity of theopioidwithdrawalsyndrome, which can cause anunwantedrelapse. Mitragynineisthemainalkaloidcompoundfound in theleaves of Mitragynaspeciosapopularlyknown as kratom, a plantwidelyusedbyopiateaddictstomitigatetheharshness of drugabstinence.

A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, it was first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway.

 

 

Mitragynine Attenuates Withdrawal Syndrome in Morphine-Withdrawn Zebrafish
Beng-Siang Khor,1 MohdFadzly Amar Jamil,1 MohamadIlham Adenan,1,2 and Alexander Chong Shu-Chien1,3,*
RamaniRamchandran, Editor

 

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