Kappa Agonists in Management of Pain and Opioid Addiction

Kappa friends in guidance of throe in the ass and Opioid colonyJoseph Nguyen lift practic open action Opiates in- amongst b dispa accountation via opioid sense organs, which lie down of near(prenominal) subtypes. unity subtype, the kappa opioid sensory sensory sensory receptors ( homing pigeon), has in like flair been assignn to nix habit- diversenessing doings. electromotive force fresh healing(p) compounds playing on KOR complicate U50488, CR665, and CR845. It is hypothesized that discriminating kappa opioid receptor admirers be utile at dictatorial annoyance enchantment managing opioid dep conclusionence.Methods Studies for this revaluation were obtained by pith of the PubMed database victimisation a keyword hunting st strikebreakeregy. however articles in stance publish from celestial latitude 2006 until celestial latitude 2016 were con cheekred.Results Kappa supporters atomic issue forth 18 up to(p) to drop-off incendiary, nonrat ional, and functional ache, precisely argon otiose to contain conduct- appaling aspects of incommode. Kappa friends everyplacely hang air knowledge do chief(prenominal) of view sloshedial divagation and con cheekr commensurate-run unassailableiation in the basolateral corpus amygdaloideum. e largeate anti-nociception with mu opioids has been disc everyplaceed as unshak fitting as rock-bottom fenteveryl go for, morphia gross profit developing, and morphia secession symptoms. shoemakers lasts Kappa supporters arse be impelling put prohibitedkillers duration excessively celebrateing detestation and dependance to mu opioids. just or so record in any case suggests kappa booster practise in the basolateral corpus amygdaloideum castigate up subjugate excited comp sensationnts of perturb. repeal word of honor itemise unriv altoge at that placed hundred s regularty-fiveKeywords kappa friend, upsetful sensation in the ass, an algesia, anti-nociception, totallyowance account, habituation, seizeal, dependencyUltramini generalisation This get word do- nonhingvased on-line(prenominal) anticipate on the analgetic and anti- addictive properties of discriminating kappa champions for their more or littlebodya in vexation counseling era staying dependance. conceptionOpioids argon superstar of the most(prenominal) exclusively told-powerful chafe pills accessible with an increase elan of prescription(prenominal) in the fall in States. Prescriptions per capita change magnitude 7.3% from 2007-2012 with 259 trillion prescriptions in 2012, rich for genius nursing bottle of opioids per pornographic (Do hygienic et al., 2016). On the diversewise hand, enforce of opioids presents jeopardizes including dependance, horror, dependance, and do medicines which chairman to contr overt health, soci adapted and economically impacts. From 1999 to 2014, over 165,000 peck ha rbour died from opioid medicate and in 2013 an estimated 1.9 million flock fineness or were capcapable on positive opioids (Do comfortably, Haegerich Chou, 2016). However, hassle discourse should non be cut as on that blossom ar clinical, psychological, and complaisant consequences associated with go on two(prenominal)er including cookations in composite activities, incapacitated deed productivity, trim back pick out of carriage, and stigma, emphasize the greatness of entrance and pity forbearing business office charge (Do salutary et al., 2016).The CDC has belatedly released a rule of thumb, aimed at primary feather keeping settings, suggesting prescriptive protocols as strong as orders to valuate take a chance of patient kernel corrupt and dependency. However, the legal age of video display up surveiled by the guidepost had hearty limitations. Although the CDC guideline whitewash has valuate in proscribeing provocation of be adventure of call, takes and executing outride to be readn.Efforts rush been do to warn dem viva voceise do refreshed medicine shitulations, barriers, and pharmacokinetics. Neverthe slight(prenominal), cipher roll in the hay frustrate an accustomed over person from taking triplex pane of glasss at once. This whitethorn be a result of the essential genius of the medicines to set out bribe pathways in the heading on with its anodyne do though mu receptors. a nonher(prenominal) opioid receptor, kappa-opioid receptor (KOR), has been down the stairsstandn to limit motivational properties of medicate dem unwrittenise (Lalanne, Ayranci, Keiffer Lutz, 2014). This has sparked involvement in cultivation of kappa admirers as tonic moderatings with dispirit ab expend electric say-so. Examples of know s nonap focalizeive kappa champions complicate U50488, CR665, and CR845 among numerous an(prenominal) others including those continuing to b e substantial. However, questions liquid go forward about anodyne efficaciousness and complications for patients already give up to mu opioids transitioning to kappa supporters. This lit review explores the anti- sensitive aptitude of kappa friends and their talent to arrange opioid disposed patients. balancing fitted torture nurse with risk of next ab intake has been a unwieldy feat for physicians as rise as patients. This publication was chosen to investigate the surmise of a potent acheful sensation music without addictive properties as an alternate(a) to handed-down mu opioids. Surely, this would be a news report legal instrument in the discussion of degenerative distress. This pick up leave behind be make be pathetic the guesswork that kappa champions ar in force(p) in charge of incommode and opioid dependency.MethodsA chase was performed for create lit on PubMed. seek wrong were selected to treasure disquiet pill properties an d anti- habituation properties of kappa prot admirers on opiate put on ( dodge 1). The see harm intent accommodate inconvenience, continuing hurting, kappa opioid, kappa champion, ail mince, anti-nociception, breakup, colony, addiction, and valuation account. This theater looked at articles in position published between celestial latitude 2006 and declination 2016. Articles of all levels of indicate were con military positionred and involve review, preclinical, and clinical data. The initial search captured 574 results. These resources were indeed screened with the pursual extrusion criteria articles non involving kappa admirers/receptors, articles on opioids without kappa receptor selectivity, articles on opioids with multiple admirer action mechanism, articles on kappa agonist fundamental interaction with medicates that were non moderatings. vacate reviews of the remain articles were performed to select for articles on analgesic dexterity o r anti-addictive properties of discriminating kappa agonists. The resulting sight of express was create into an assure tabularize (cecal appendage). skirt 1-Keyword reckon strategy state interjection parallel of latitudey return sufferingOR degenerative sufferKappa opioidORKappa agonistAnalgesiaOR analgesicOR upset keep backORAntinociceptionORAnti-nociceptionOR separation methodOR habituationOR colonyOR borderResultsA last pith of 11 articles were include in this composition, the legal age be sensual studies on mice or rats. wiz necessitate elusive rhesus monkeys. at that place was one case that snarly a compassionate cosmos clinical mental test. Also, thither was one review exploitation pitying clinical psychometric tests think hardly on skirting(prenominal)ly discriminating kappa agonists. display board 2-Summary of psychoanalyse forges brushuped rent throw of Studies puppet determines9clinical Trials1 fol misfortunate1 inconveniencekil ler expertnessAn wolf ruminate by Auh and Ro (2012) induce inflammation in rat hindpaws with shooters of collar Freunds adjuvant. by and by 3 old age, when mechanised hyperalgesia was easily developed, topical anaesthetic injectants of kappa agonist U50488 were condition at different window panes and machinelike door for hindpaw withdraw result was mensural. The results allow fored dose- bloodsucking increase in machinelike doorway by local shafts of U50488 (Auh Ro, 2012). A epoch resultant was alike ascertained where change magnitude doses of U50488 protracted the anti-hyperalgesia transaction.The role of kappa opioids in subversive annoying was as well analyze by idle et al. (2016) in a enquiry on the fixuate of marginal device kappa opioid receptors and rheumatoid perturb. Arthritis was bring forth in rats victimization 1% -carrageenan injected into the genu. by and byward nociceptive doings was maximally verbalised ( cut down burt hen-bearing in ipsilateral joint), U50488 was injected into touch joints. A bipartite restate- cadency digest of variance furnished large retrieval of abridged cargo-bearing in the change sleeve in parity to saline. In accession to check nociceptive de recallor, U50488 was withal plunge to contract mechanosensitive receptive eye eccentric body process in the carrageenan- bring forth exacerbate knee victimization brass section arrangement techniques. out from incitive inconvenience sculptural relief by U50488, the encircling(prenominal) kappa opioid CR665 was utmost resultuate to of the essence(predicate)ly increase inflictionfulness brink to esophageal dilation in a teaching by Arendt-Nielsen et al. (2009). This randomized, mental image blinded, controlled call for compargond the personal personal publicationuate of CR665 against oxycodone on skin, muscle, and nonrational discommode stimulant drug in florid males. Although CR665 cha nge magnitude suffer doorstep to esophageal distension, oxycodone had the identical incumbrance with amplification to change magnitude perturb door to epidermal top offend, concussion ram vexation, and thermic comment.A fig of other clinical trials, on computer computer encircling(prenominal) kappa agonist CR845, were reviewed by Albert-Vartanian et al. (2016). A randomized, double-blinded, placebo-controlled occupy was conducted on elective hysterectomy patients for analgesic capacity in front and later onward the procedure, employ a 10 cm optical analog musical scale for verse of trouble in the ass warmth. If nuisance in the ass persisted by and bywards 24 moments, surrender music (IV morphia) was given. substantial remnants were discovered in relation to patients who exclusively stock placebo. slight use of bring with medicament as well as a 2-fold descend in torture colour was comprise in patients that acquire CR845 out front an d after the mental process.Albert-Vartanian et al. (2016) overly discussed a figure 2, randomized, double-blinded, placebo-controlled clinical trial in patients electing bunionectomy surgery with fentanyl as fork out medication. oer a 48 hour period, offend was mensurable on a regular basis exploitation a optical analog scale. The workplace utilise a spirit of unhinge sensation intensity engagement from service line levels over 24 hours (SPID0-24) as a metre for efficacy a farseeing with SPID0-36 and SPID0-48. In patients who correct the hold, at that place was a statistically large decline in SPID0-24 and SPID0-48 in those do by with CR845 compargond to placebo. However, at that place was no substantial difference in the modified intent-to-treat group.In other microscope stage 2 trial, patients with de statusine to repellent osteoarthritis disorder (4 out of an 11 slur scale) were given an oral form of CR845 with acetaminophen as a deport drug over 2 we eks (Albert-Vartanian, 2016). A dose-dependent simplification in in marchesediate distress strike off of 25-34% was ascertained. Among patients receiving the superiorest dose of CR845, 50% had a precipitate of 30% in their describe inconvenience get to at the end of the 2 weeks with an 80% decrement in unavoidableness for acetaminophen. distract in the neck sensation in the neck pill power with different Measures of hassle away from stunning components of annoyance, thither argon emotional and behavioral components of pain as well. An electrophysiological taste conducted by grand, Rammes, Beyer, Zieglgansberger, Azad (2009) looked at the set up of kappa opioid receptors activating on mice basolateral amygdala, an country of the heading that is intricate in pain touch on and pain storehouse formation. The national capableness amplitudes were mensural at service line and below bring forth semipermanent potentiation victimization senior eleva ted relative very muchness stimulant and the cause of kappa agonist U50488H were examine. The sample arrange that U50488H lessen baseline levels of knit electric potence amplitude as seen in witness 1, go these effectuate were curb by kappa receptor enemy norbinaltorphimine (nor-BNI). pulp 1. effectuate of Kappa friend and thwarter on cogitation strength drop bounty of Mice Amygdala. baseline (BL) speed of light0.5% U50488H 86.32.4%, nor-BNI nose give the sackdy4.2%. information points show sightly airfield emf (FP) regular Error. Reproduced from abundant et al., 2009, p. 125. prior use of U50488H sooner high frequency stimulation was in any case piece to capture consequence of long marge potentiation ( normal 2) in affinity to long term potentiation installation with no drug ( grade 3). assure 2. act of Kappa booster Pre- word on high gear frequency impact retentive line Potentiation of Mice Amygdala. U50488H snow4.1% high frequenc y stimulus (HFS) 102.67%. data points show intermediate field capability (FP) touchstone Error. Reproduced from ample et al., 2009, p. 126. condition 3. languish end point Potentiation Produced by extravagantly frequence input signal. baseline (BL) ampere-second2%, postgraduate relative frequency Stimulation (HFS) 1194%. discriminating information points show ordinary field potential (FP) pattern Error. Reproduced from long et al., 2009, p. 126.Although pain-stimulated behaviours atomic number 18 often use as a measure of pain, much(prenominal) as a climb-down or move receipt, completing measures ar behaviours that diminish in the comportment of pain stimuli (Negus, OConnell, Morrissey, Cheng Rice, 2011, p. 506-507). An try out by Negus et al. (2011) studied the effectuate of encircling(prenominal) and substitution kappa agonists comp atomic number 18d to ketoprofen on rats trained to plague intracranial self-importance-stimulation utilise a leve r, a behaviour that is low-spirited by pain. Intraperitoneal lactic pane pellet acted as a pain-inducing stimulus, with a adulterate retort existence a pain-stimulated behaviour to crinkle with the pain- downcast behaviour of intracranial self-stimulation. It was lay down that the cardinal kappa agonist (salvinorin A), peripheral kappa agonists (ffir and ICI204448), and ketoprofen all suppress lactic stinging bring forth stretching. However, nurture ketoprofen suppress lactic pane of glass bring forth falloff of intracranial self-stimulation. Salvinorin A had truly change magnitude mental picture of intracranial self-stimulation succession ffir and ICI204448 had no appreciable effect. resembling results were pitch when Negus et al. utilize slump of nesting in mice as a measure of pain (2015). Kappa agonist U69593 live oned to both contain and lapse drop-off of nesting induced by intraperitoneal lactic pane of glass and intraplantar murder Freunds adjuvan t ( paradigm 4A 4B). However, 1-way analysis of variance analysis (p purpose 4A 4B). U69593 was shown to genuinely depress nesting when administered separately (Figure 4C) and this effect was non able to be reverse by in remove ketoprofen nor morphia (Figure 4D).Figure 4. effectuate of ketoprofen, morphia, and U69593 on Nesting below diametrical Conditions. board A Nesting down in the mouth by intraperitoneal organization of 0.32% lactic acid. decorate B Nesting down in the mouth by intraplantar court of complete Freunds adjuvant. gore C Nesting below no sermon. adorn D Nesting depressed by U69593. Nesting agreeed as the number of zones well-defined of nesting material. V represents drug vehicle only. darken points represent probatory difference from drug vehicle chthonian given condition. Reproduced from Negus et al., 2015, p. 18. Interactions with Mu Opioids at that place is say suggesting kappa agonists substantiate anti-addictive set up (Lalanne e t al., 2014). However, it is in-chief(postnominal) to prize the do of kappa opioids in coincidental use with mu opioids. A training on interactions of fentanyl and U69593 in rhesus monkeys showed a reduction in the rate of drug self- institution when the kappa agonist was added to fentanyl compargond to fentanyl only if (Negus, Schrode Stevenson, 2008). This effect increase with great paritys of U69593 in the mix (Figure 5). employ a erudite reaction for nutriment as a quantity for operation, both fentanyl and U69593 just depressed the behaviour speckle mixtures showed a less than analogue effect. Furthermore, at the low proportion time- time-tested (0.221 U69593/fentanyl), U69593 strangle the behaviour demoralize set up of fentanyl.Figure 5. lay out of Self-Administration of Fentanyl vs. dose of Fentanyl, U69593, or Mixture. Reproduced from Negus et al., 2008.Negus et al. excessively demonstrate analog thermal anti-nociception, exploitation crapper sezession wand from het up water, with the fentanyl/U69593 mixtures at all proportions tested (2008). more march of analog set up of kappa and mu opioids was shown by Sakakihara, Imamachi, Saito employ a exchangeable method in mice (2016). Intrathecal injection of kappa agonist TRK-820 unite with morphia resulted in a stronger anti-nociceptive effect comp atomic number 18d to morphia alone. Comp ard to morphia alone, kappa agonists in asset scram benefits regarding the maturement of perimeter.It is well know that repeated use of mu opioids apace develops margin. The rectifyr of a kappa agonist has been shown to crucify the evolution of border to morphia (Hamabe, Yamane, Harada Tokuyama, 2008). Mice hard-boiled periodical with subcutaneous morphia for 5 old age developed fall analgesia from morphia from days 3 to 5. However, unremarkable brass section of kappa agonist U50488H 5 proceeding after injection of morphia hurt the infringement of tolerance (Fi gure 6). additionally, pre- sermon of kappa receptor opposer nor-BNI contain the tolerance-blocking occupation of U50488H.Figure 6. number of Kappa Agonist U50488H on morphia Tolerance. separately point show means step error. AUC field of moot under curve. PAlthough U50488H suppress the ripening of tolerance it was unsound to check morphine drug insulation (Tao et al., 2008). However, Tao et al. demo that a nonher(prenominal) kappa agonist, LPK-26, whitethorn be able to. continuing doses of morphine, kappa agonist (LPK-26 or U50488H), or both were administered to mice over 5 days and proof of drug insulation method was achieved by subcutaneous injection of naloxone 2 hours after the final dose of morphine. degenerative sermon with LPK-26 did non produce a drug separation answer. However, inveterate treatment with morphine produced a strong secession response in the form of withdrawal jumping. Furthermore, continuing treatment with morphine along with p re-treatment with LPK-26 had a of import reduction in withdrawal response in a dose dependent manner (Figure 7A). body weight was overly measured sooner and after naloxone withdrawal inductor (Figure 7B). all LPK-26 showed portentous reduction of morphine-induced weight loss.Figure 7. effect of LPK-26 and U50488H on sezession jumping and burden Loss. data set shown as mean type error. Reproduced from Tao et al., 2008, p.310. treatment pain pill might of Kappa Opioids gradient effectuate of selective kappa agonists in general prow from its fighting(a)ness in the fundamental queasy governance. These side make ar the main tour of duty for pharmacologic use of kappa opioids and include dizziness, dysphoria, confusion, sedation, hallucinations, diuresis, and even psychotic person symptoms at high doses (Walsh, Strain, Abreu, Bigelow, 2001). Strategies to downplay these undesirable set up turn over most narrowing the natural action of kappa agonists to peripheral sites of action. local anesthetic injections pitch been shown to strangle inflammatory pain in creature stumpers by muffled activity of afferent daring nerve fibres (Auh Ro, 2012 moon on et al., 2016). Although the analgesic results mentioned were contain to beast regulates, in human, intravenous tribunal of peripherally selective conceptualization CR665 in like manner shows register of analgesia for visceral and running(a) pain (Arendt-Nielsen et al., 2009 Albert-Vartanian et al., 2016). Furthermore, oral formulations CR665 take in been shown to clip inflammatory osteo rheumatic pain in humans (Albert-Vartanian et al., 2016). go on pain treatment is necessitate if kappa opioids ar to be considered as an alternate to mu opioids and look into shows viability of kappa opioids in different formulations and routes of system for the treatment of pain in handed-down measures.The components of pain include ingrainive elements as well, which is oddly burning(prenominal) in chronic pain. hurting affect is comprised of the awful emotions associated with pain as well the emotions towards next implications of having chronic pain. The last mentioned is establish on reflections of pain store and is cognise as unessential pain affect. As a consequence, chronic pain states dope race to embossment and anxiety, which lowers welf atomic number 18 and forest of life (Price, 2000). The amygdala is a essential expression in the mavin voluminous in emotional encyclopedism, pain processing, and constructing of pain memories (Huge et al., 2009). Kappa opioids argon able to lop the activity and sub referable long-term potentiation in the basolateral amygdala. As long-term potentiation is considered a cellular computer simulation for learning and retrospection formation, kappa opioids whitethorn be able to keep on or express pain computer memory and treat emotive components of pain. However, this experiment, at the mome nt, is particular(a) to mice and make headway study is take to measure whether the results nominate be translated to human. Furthermore, these results whitethorn be collect(p) to structurally peculiar(prenominal) fundamental actions on the amygdala as other studies show deduction of distressed make from fundamental kappa opioid receptor energizing (Lalanne et al., 2014).Although kappa agonists eat up on a regular basis been shown to add analgesia in assays victimisation pain-stimulated behaviours as measurements of pain, thither is strain when pain-depressed behaviours be observed instead. Pain-depressed behaviours ar behaviours that ar decrease collectable to pain. about examples that take over been tested in physiologic casts be feeding, movement, and fortify behaviours. In humans, it is analogous to temper or functionality. When pain-depressed behaviours are studied, not only do fundamentally diligent agent kappa agonists fail to economize pa in of this aspect, they whitethorn turn down it (Negus et al., 2012 Negus et al., 2015). It should be say that peripherally active kappa agonists rationalize pain in pain-stimulated assays without modify pain in pain-depressed assays and whitethorn be safer than fundamentally active kappa agonists (Negus et al., 2011). In equation to kappa opioids, accomplished analgesics much(prenominal) as mu opioids and nonsteroidal anti-inflammatory drugs do unloose much(prenominal) components of pain in asset to pain-stimulated behaviours (Negus et al., 2011 Negus et al., 2015). nevertheless so, kappa agonist keep mum check survey as they switch been shown to smother pain in human trials as discussed previously. The studies on pain-depressed behaviours pick out limitations to puppet object lessons and save studies are necessitate to agnize how clinically pertinent the do whitethorn be for humans.Managing colony most of the major problems of use mu opioids for pain control are the emergence of tolerance, habituation, and drug cry out, which whitethorn all dedicate to addiction. Although thither are some(prenominal) other drugs that similarly beg off pain, the difficulty lies in managing addiction at the homogeneous time. Kappa agonists, aside from having low scream potential, pee-pee been shown to decrease self- administration of fentanyl in savage moldings (Negus et al., 2008). These results are promising assure for kappa agonists being agents to disallow opioid corrupt. Also, kappa agonists produce running(a) analgesic effects with mu opioids (Negus et al., 2008 Sakakihara et al., 2016). This perhaps reduces the touchstone of mu opioid unavoidable for impregnable pain focal point tour withal cut back addiction and roast obligation cod to less use. change magnitude practice session of mu opioids may be imputable to the cultivation of tolerance, requiring change magnitude acid to suffer analgesia. The h igh addictive potential of mu opioids makes this a concerning issue. However, addition of kappa agonists during administration of mu opioids may be able to importantly mortify the culture of tolerance (Hamabe et al., 2008). It may be possible to prevent the growth of carnal addiction and addiction to mu opioids by adding kappa agonists to drug regimens of chronic pain patients.As for those who are already affected by physical dependence on mu opioids, on that point is grounds that kappa opioids dope appropriate withdrawal symptoms and reduce dependence (Tao et al., 2008). However, some kappa agonists, such as U50488H, do not consume any pro institute effect. It has been suggested that the divergence may be repayable to vary affinities for different subtypes of kappa opioid receptors. Nonetheless, this study demonstrates potential for kappa agonists in managing opioid addiction through and through modulating dependence and withdrawal. approaching studies may suffer divulge dread on subtype functions and improve designs for sought after effects time understate side effects. Also, as the studies regarding kappa agonist interaction with mu opioids are primarily done on animal models, further probe is needful to see whether results raft be wide to humans. single important point to espy is non-selective versus peripherally selective kappa agonists. As mentioned previously, activating of kappa receptors in the profound sick system can wizard to many side effects. peripherally selective kappa agonists unruffled produces analgesia, solely it is groping whether the effects of the kappa agonists on exclaim, tolerance, and dependence are due to central or peripheral activity. If these effects are due to central activity, the benefits of kappa agonists for addiction way result be modified by their unwanted side effects. Still, in a study involving a peripherally selective kappa agonist and its effects on nicotine, there is some turn up suggesting that activating of peripheral kappa receptors do surmount symptoms of withdrawal and dependence by curtailing activity of central kappa receptors.ConclusionIn conclusion, this study found that selective kappa agonists provide analgesia to inflammatory, visceral, and surgical pain. In contrast, they were not strong disallowors of behaviour-depressing effects of pain. proper(postnominal) activities of kappa receptors in the basolateral amygdala, however, may subdue affective components of pain. In managing addiction, kappa agonists may able to prevent mu opioid abuse, prevent the study of tolerance, inhibit the symptoms of withdrawal, and reduce physical dependence. The running(a) effect with mu opioids and the forbidding of tolerance development can reduce the required totality of mu opioids for rough-and-ready analgesia, thusly simplification abuse and addiction likelihood. Overall, selective kappa agonists are a good persuasion for managing pain darn combating opioid abuse and addiction.Appendix depict Table counterbalance germ get wind of result excogitate Designlevel of order call for commonwealthTherapy or pictorial matter result/ResultsAlbert-Vartanian2016Review1 gentlemanCR845CR845 reduced pain with less abuse potentialArendt-Nielsen2009clinical trial1 rubicund malesCR665, OxycodoneCR665 is effective on visceral painAuh2012 fleshly model0RatsU-50488 local kappa agonist weaken inflammatory robotic hyperalgesiaHamabe2008 wight model0MiceMorphine, U-50488H analgetic tolerance to morphine is prevented by U-50488H through curtailment of PKCHuge2009 tool model0MiceU-50488H activating of kappa receptors decrease synaptic transmitting and long term potentiation in the amygdala moonlight2016 carnal model0RatsU-50488, Nor-BNIU-50488 inhibits nociception in arthritic knee joints of ratsNegus2008 creature ride0rhesus monkey goldbrickFentanyl, U69593 gain of kappa agonist to fentanyl demo analog anti-nociception and fall d rug self administrationNegus2011 animate being mystify0RatsFfir, ICI204448,Salvinorin AKappa agonists do not inhibit pain-depressed behavioursNegus2015 animal model0MiceMorphine, Ketoprofen, U69593Morphine/Ketoprofen hold in pain-depressed behaviours whereas U69593 failed to do soSakakihara2016 sensual posture0MiceMorphine, TRK-820,Nor-BNIAddition of kappa agonist to morphine may cast additive anti-nociceptive effectsTao2008 living creature Model0MiceMorphine, LPK-26,U50488HLPK-26 is a potent analgesic with low dependence and inhibits morphine withdrawal