Reddit kappa

Kappa Meme

colorful kappa graphic

About

Kappa is a graphic emoticon commonly used by trolls as a postscript to a sentence to convey sarcasm on the live streaming video platform Twitch; it's popularity has also lead to the emoticon being used as a form of spam.

Origin

The Kappa emote is based on a grey-scale photograph of Josh DeSeno, then an employee of Justin.TV working on the chat client, which was uploaded during the early days of Justin.TV, along with others emotes based on JTV employees.

Hearthstone face person chin eyebrow forehead cheek nose hairstyle head jawBattlefield 1 T-shirt face eyebrow facial expression forehead chin cheek black and white nose head monochrome photography hairstyle jaw portrait

Spread

As of February 2014, the emote is used 900,000 times on average per day; by June 2015 this had already increased to around 1 million times on average per day. Twitch has added a total of four emotes featuring Kappa: Kappa (), Keepo (), MiniK () and KappaHD (); another unique Kappa titled KappaRoss (Bob Ross headgear head forehead hat ), featuring the original with Bob Ross' hair, was added in October 2015 in celebration of Twitch Creative. On February 18th, 2012, r/kappa/subreddit was established. It has got over 13,900 readers. On July 13th, 2014, first submission for Kappa on Urban Dictionary was made, and on October 13th, the top definition of the "Kappa" emote was submitted by R4D1AT10N.

KappaClaus

In December of 2015, Twitch introduced the KappaClaus emote, a version of the Kappa emote with a Santa Claus hat on his head (shown below). The emote has typically seen an increase in use around December.


Dota 2 face nose forehead headgear fashion accessory head hat

KappaPride

KappaPride is a Twitch emote featuring Kappa with a rainbow background used to affirm or inquire about one's homosexuality. A thread about the emote was posted to Bungie forums in October of 2015. In October of 2015, a study by FiveThirtyEight found that the emote was the second most-used emote on Twitch behind regular Kappa. On November 15th, 2016, Urban Dictionary user defined it as "Rainbow version of twitch emote Kappa. Can be used to affirm or ask about someone's homosexuality." There are several variations on the image available on Twitch.

T-shirt

ASCII Variation

There's also a popular ASCII used as a replacement for emoticon variantion:

░░░░▄▀▀▀▀▀█▀▄▄▄▄░░░░
░░▄▀▒▓▒▓▓▒▓▒▒▓▒▓▀▄░░
▄▀▒▒▓▒▓▒▒▓▒▓▒▓▓▒▒▓█░
█▓▒▓▒▓▒▓▓▓░░░░░░▓▓█░
█▓▓▓▓▓▒▓▒░░░░░░░░▓█░
▓▓▓▓▓▒░░░░░░░░░░░░█░
▓▓▓▓░░░░▄▄▄▄░░░▄█▄▀░
░▀▄▓░░▒▀▓▓▒▒░░█▓▒▒░░
▀▄░░░░░░░░░░░░▀▄▒▒█░
░▀░▀░░░░░▒▒▀▄▄▒▀▒▒█░
░░▀░░░░░░▒▄▄▒▄▄▄▒▒█░
░░░▀▄▄▒▒░░░░▀▀▒▒▄▀░░
░░░░░▀█▄▒▒░░░░▒▄▀░░░
░░░░░░░░▀▀█▄▄▄▄▀░░░░
░░░░░░░░░░░░░░░░░░░░


Read Full Entry

The latest from KYM

Meme

About a week ago, this pop-punk adjacent jingle got stuck into the internet's head started from an October 12th TikTok. TikTokers started singing the 'Burger Queen' anthem in their own videos, spreading the lyrics as a catchphrase to other platforms.

Oct 21st, 2021 11:27 AM

Trending

Meme

The annual trend of putting increasingly absurd things inside Halloween candy and making PSAs about it started in 2011 with Jacksfilms and is still very alive to this day.

Oct 21st, 2021 11:29 AM

Trending

Meme

"Only '90s Kids" is a series of memes in which the punchline can be genuine nostalgia-bait or an ironic take on the thinking that only '90s kids are able to have certain experiences or understanding. Existing in multiple forms for over 15 years, this catchphrase has gone through many meme phases multiple times.

Oct 21st, 2021 08:35 AM

Researching

Sours: https://knowyourmeme.com/memes/kappa
I have noticed many similarities between this board and r/Kappa.

-They hate SF5.
-They hate Capcom.
-Often have been claimed as not having actually played the fighting games they maliciously joke about and hate.
-Openly mock and belittle the FGC and its practices.
-Sometimes claim to be the people who wish to shape and "save" the FGC.

Opinions? Are they the "true" FGC? Or are they just a bunch of s***posters who only wish to sow chaos and disorder among the community?

SF5: M. Bison, Urien, Seth, Akira | GGST: Leo
Mankind knew that they cannot change society, so instead of reflecting on themselves, they blamed the developers.

The Wasteland or Wastes refers to the majority of the world's post-nuclear environment in the Fallout universe.

"Equivalent exchange, you syrup demon."

Only thing I know about r/kappa is that Daru I-No claims them. So they're probably not that cool.

Oh, and it's reddit and kappa, so probably full of idiots.

GGS - Faust | Nick Brawl - April O'Neil | KoF02UM - Mai/Kasumi/Vice | GGXXAC+R - Testament

saint311 posted...
Daru I-No

Who?

SF5: M. Bison, Urien, Seth, Akira | GGST: Leo
Mankind knew that they cannot change society, so instead of reflecting on themselves, they blamed the developers.

Vulcan422 posted...

Openly mock and belittle the FGC and its practices.


Well they can't be all that bad then.

Lurked in the place a few times. They seem more interested in porn than in FGs. That seems to be the one notable difference between this place and r/Kappa.

Super Mario Maker 2 ID: V50-YX1-NKG
8/8/18 - K. Rool in Smash; 6/11/19 - Banjo & Kazooie in Smash; 3/24/21 - RIP KOF's storyline integrity

marchefelix posted...
Lurked in the place a few times. They seem more interested in porn than in FGs. That seems to be the one notable difference between this place and r/Kappa.

this board isn't filled with porn because gamefaqs is smart enough to stop sin and the only one here who wouldn't post wack s*** is prettytonytiger

"Equivalent exchange, you syrup demon."

r/kappa was great in the usf4-era

nowadays, the subreddit is a porn dump and flame war

https://a.pomf.cat/koctbt.mp4

Sours: https://gamefaqs.gamespot.com/boards/208-fighting-games/76734623
  1. Hien van spa videos 2021
  2. Naruto kurama
  3. Reach halo

Inter-Rater Reliability Measures in R

Cohen’s Kappa in R: For Two Categorical Variables

Cohen’s kappa(Jacob Cohen 1960, J Cohen (1968)) is used to measure the agreement of two raters (i.e., “judges”, “observers”) or methods rating on categorical scales. This process of measuring the extent to which two raters assign the same categories or score to the same subject is called inter-rater reliability.

Traditionally, the inter-rater reliability was measured as simple overall percent agreement, calculated as the number of cases where both raters agree divided by the total number of cases considered.

This percent agreement is criticized due to its inability to take into account random or expected agreement by chance, which is the proportion of agreement that you would expect two raters to have based simply on chance.

The Cohen’s kappa is a commonly used measure of agreement that removes this chance agreement. In other words, it accounts for the possibility that raters actually guess on at least some variables due to uncertainty.

There are many situation where you can calculate the Cohen’s Kappa. For example, you might use the Cohen’s kappa to determine the agreement between two doctors in diagnosing patients into “good”, “intermediate” and “bad” prognostic cases.

The Cohen’s kappa can be used for two categorical variables, which can be either two nominal or two ordinal variables. Other variants exists, including:

  • Weighted kappa to be used only for ordinal variables.
  • Light’s Kappa, which is just the average of all possible two-raters Cohen’s Kappa when having more than two categorical variables (Conger 1980).
  • Fleiss kappa, which is an adaptation of Cohen’s kappa for n raters, where n can be 2 or more.

This chapter describes how to measure the inter-rater agreement using the Cohen’s kappa and Light’s Kappa.

You will learn:

  • The basics, formula and step-by-step explanation for manual calculation
  • Examples of R code to compute Cohen’s kappa for two raters
  • How to calculate Light’s kappa for more than two raters
  • Interpretation of the kappa coefficient


Contents:

Related Book

Inter-Rater Reliability Essentials: Practical Guide in R

Basics and manual calculations

Formula

The formula of Cohen’s Kappa is defined as follow:

Cohen’s Kappa formula

  • Po: proportion of observed agreement
  • Pe: proportion of chance agreement

kappa can range form -1 (no agreement) to +1 (perfect agreement).

  • when k = 0, the agreement is no better than what would be obtained by chance.
  • when k is negative, the agreement is less than the agreement expected by chance.
  • when k is positive, the rater agreement exceeds chance agreement.

Kappa for 2x2 tables

For explaining how to calculate the observed and expected agreement, let’s consider the following contingency table. Two clinical psychologists were asked to diagnose whether 70 individuals are in depression or not.

Data structure:

Where:

  • a, b, c and d are the observed (O) counts of individuals;
  • N = a + b + c + d, that is the total table counts;
  • R1 and R2 are the total of row 1 and 2, respectively. These represent row margins in the statistics jargon.
  • C1 and C2 are the total of column 1 and 2, respectively. These are column margins.

Example of data:

Proportion of observed agreement. The total observed agreement counts is the sum of the diagonal entries. The proportion of observed agreement is: , where N is the total table counts.

  • 25 participants were diagnosed yes by the two doctors
  • 20 participants were diagnosed no by both

so,

Proportion of chance agreement. The expected proportion of agreement is calculated as follow.

Step 1. Determine the probability that both doctors would randomly say Yes:

    1. Doctor 1 says yes to 35/70 (0.5) participants. This represents the row 1 marginal proportion, which is .
    1. Doctor 2 says yes to 40/70 (0.57) participants. This represents the column 1 marginal proportion, which is .
    1. Total probability of both doctors saying yes randomly is . This is the product of row 1 and column 1 marginal proportions.

Step 2. Determine the probability that both doctors would randomly say No:

    1. Doctor 1 says no to 35/70 (0.5) participants. This is the row 2 marginal proportion: .
    1. Doctor 2 says no to 30/70 (0.428) participants. This is the column 2 marginal proportion: .
    1. Total probability of both doctors saying no randomly is . This is the product of row 2 and column 2 marginal proportions.

so, the total expected probability by chance is . Technically, this can be seen as the sum of the product of rows and columns marginal proportions: .

Cohen’s kappa. Finally, the Cohen’s kappa is .

Kappa for two categorical variables with multiple levels

In the previous section, we demonstrated how to manually compute the kappa value for 2x2 table (binomial variables: yes vs no). This can be generalized to categorical variables with multiple levels as follow.

The ratings scores from the two raters can be summarized in a k×k contingency table, where k is the number of categories.

Example of kxk contingency table to assess agreement about k categories by two different raters:

Terminologies:

  • The column “Total” () indicates the sum of each row, known as row margins or marginal counts. Here, the total sum of a given row is named .
  • The row “Total” () indicates the sum of each column, known as column margins. Here, the total sum of a given column is named
  • N is the total sum of all table cells
  • For a give row/column, the marginal proportion is the row/column margin divide by N. This is also known as the marginal frequencies or probabilities. For a row , the marginal proportion is . Similarly, for a given column , the marginal proportion is .
  • For each table cell, the proportion can be calculated as the cell count divided by N.

The proportion of observed agreement (Po) is the sum of diagonal proportions, which corresponds to the proportion of cases in each category for which the two raters agreed on the assignment.

Proportion of observed agreement formula

The proportion of chance agreement (Pe) is the sum of the products of the rows and columns marginal proportions:

Proportion of expected (chance) agreement formula

So, the Cohen’s kappa can be calculated by plugging Po and Pe in the formula: .

Kappa confidence intervals. For large sample size, the standard error (SE) of kappa can be computed as follow (J. L. Fleiss and Cohen 1973, J. L. Fleiss, Cohen, and Everitt (1969), Friendly, Meyer, and Zeileis (2015)):

Standard error of kappa

Once SE(k) is calculated, a confidence interval for kappa may be computed using the standard normal distribution as follows:

Confidence interval of kappa

For example, the formula of the 95% confidence interval is: .

R code to compute step by step the Cohen’s kappa:

In the following sections, you will learn a single line R function to compute Kappa.

Interpretation: Magnitude of the agreement

In most applications, there is usually more interest in the magnitude of kappa than in the statistical significance of kappa. The following classifications has been suggested to interpret the strength of the agreement based on the Cohen’s Kappa value (Altman 1999, Landis JR (1977)).

< 0Poor
0.01 - 0.20Slight
0.21-0.40Fair
0.41-0.60Moderate
0.61-0.80Substantial
0.81 - 1.00Almost perfect

However, this interpretation allows for very little agreement among raters to be described as “substantial”. According to the table 61% agreement is considered as good, but this can immediately be seen as problematic depending on the field. Almost 40% of the data in the dataset represent faulty data. In healthcare research, this could lead to recommendations for changing practice based on faulty evidence. For a clinical laboratory, having 40% of the sample evaluations being wrong would be an extremely serious quality problem (McHugh 2012).

This is the reason that many texts recommend 80% agreement as the minimum acceptable inter-rater agreement. Any kappa below 0.60 indicates inadequate agreement among the raters and little confidence should be placed in the study results.

Fleiss et al. (2003) stated that for most purposes,

  • values greater than 0.75 or so may be taken to represent excellent agreement beyond chance,
  • values below 0.40 or so may be taken to represent poor agreement beyond chance, and
  • values between 0.40 and 0.75 may be taken to represent fair to good agreement beyond chance.

Another logical interpretation of kappa from (McHugh 2012) is suggested in the table below:

0 - 0.20None0 - 4‰
0.21 - 0.39Minimal4 - 15%
0.40 - 0.59Weak15 - 35%
0.60 - 0.79Moderate35 - 63%
0.80 - 0.90Strong64 - 81%
Above 0.90Almost Perfect82 - 100%

In the table above, the column “% of data that are reliable” corresponds to the squared kappa, an equivalent of the squared correlation coefficient, which is directly interpretable.

Assumptions and requirements

Your data should met the following assumptions for computing Cohen’s Kappa.

  1. You have two outcome categorical variables, which can be ordinal or nominal variables.
  2. The two outcome variables should have exactly the same categories
  3. You have paired observations; each subject is categorized twice by two independent raters or methods.
  4. The same two raters are used for all participants.

Statistical hypotheses

  • Null hypothesis (H0): . The agreement is the same as chance agreement.
  • Alternative hypothesis (Ha): . The agreement is different from chance agreement.

Example of data

We’ll use the psychiatric diagnoses data provided by two clinical doctors. 30 patients were enrolled and classified by each of the two doctors into 5 categories (J. Fleiss and others 1971): 1. Depression, 2. Personality Disorder, 3. Schizophrenia, 4. Neurosis, 5. Other.

The data is organized into the following 5x5 contingency table:

Computing Kappa

Kappa for two raters

The R function [vcd package] can be used to compute unweighted and weighted Kappa. The unweighted version corresponds to the Cohen’s Kappa, which are our concern in this chapter. The weighted Kappa should be considered only for ordinal variables and are largely described in Chapter @ref(weighted-kappa).

Note that, in the above results is the asymptotic standard error of the kappa value.

In our example, the Cohen’s kappa (k) = 0.65, which represents a fair to good strength of agreement according to Fleiss e al. (2003) classification. This is confirmed by the obtained p-value (p < 0.05), indicating that our calculated kappa is significantly different from zero.

Kappa for more than two raters

If there are more than 2 raters, then the average of all possible two-raters kappa is known as Light’s kappa(Conger 1980). You can compute it using the function [irr package], which takes a matrix as input. The matrix columns are raters and rows are individuals.

Report

Cohen’s kappa was computed to assess the agreement between two doctors in diagnosing the psychiatric disorders in 30 patients. There was a good agreement between the two doctors, kappa = 0.65 (95% CI, 0.46 to 0.84), p < 0.0001.

Summary

This chapter describes the basics and the formula of the Cohen’s kappa. Additionally, we show how to compute and interpret the kappa coefficient in R. We also provide examples of R code for computing the Light’s Kappa, which is the average of all possible two-raters kappa when you have more than two raters.

Other variants of Cohen’s kappa include: the weighted kappa (for two ordinal variables, Chapter @ref(weighted-kappa)) and Fleiss kappa (for two or more variables, Chapter @ref(weighted-kappa)).

References

Altman, Douglas G. 1999. Practical Statistics for Medical Research. Chapman; Hall/CRC Press.

Cohen, J. 1968. “Weighted Kappa: Nominal Scale Agreement with Provision for Scaled Disagreement or Partial Credit.” Psychological Bulletin 70 (4): 213—220. doi:10.1037/h0026256.

Cohen, Jacob. 1960. “A Coefficient of Agreement for Nominal Scales.” Educational and Psychological Measurement 20 (1): 37–46. doi:10.1177/001316446002000104.

Conger, A. J. 1980. “Integration and Generalization of Kappas for Multiple Raters.” Psychological Bulletin 88 (2): 322–28.

Fleiss, J.L., and others. 1971. “Measuring Nominal Scale Agreement Among Many Raters.” Psychological Bulletin 76 (5): 378–82.

Fleiss, Joseph L., and Jacob Cohen. 1973. “The Equivalence of Weighted Kappa and the Intraclass Correlation Coefficient as Measures of Reliability.” Educational and Psychological Measurement 33 (3): 613–19. doi:10.1177/001316447303300309.

Fleiss, Joseph L., Jacob Willem Cohen, and Brian Everitt. 1969. “Large Sample Standard Errors of Kappa and Weighted Kappa.” Psychological Bulletin 72: 332–27.

Friendly, Michael, D. Meyer, and A. Zeileis. 2015. Discrete Data Analysis with R: Visualization and Modeling Techniques for Categorical and Count Data. 1st ed. Chapman; Hall/CRC.

Landis JR, Koch GG. 1977. “The Measurement of Observer Agreement for Categorical Data” 1 (33). Biometrics: 159–74.

McHugh, Mary. 2012. “Interrater Reliability: The Kappa Statistic.” Biochemia Medica : Časopis Hrvatskoga Društva Medicinskih Biokemičara / HDMB 22 (October): 276–82. doi:10.11613/BM.2012.031.



Recommended for you

This section contains best data science and self-development resources to help you on your path.

Coursera - Online Courses and Specialization

Data science

Popular Courses Launched in 2020

Trending Courses

Amazon FBA

Amazing Selling Machine

Books - Data Science

Our Books

Others

Version: Français

Back to Inter-Rater Reliability Measures in R

Teacher

Alboukadel Kassambara
Role : Founder of Datanovia

Read More
Sours: https://www.datanovia.com/en/lessons/cohens-kappa-in-r-for-two-categorical-variables/

Kappa Alpha Theta

There are many organizations we can join as collegians and alumnae. But Theta isn't like other organizations. Our members are different; we aren't afraid to stand out, to make a difference together. Find out more about how Theta is committed to fighting racism, discrimination, and inequity—both within our sisterhood and within our world.

Read More About Our DEI plan

Joining Theta

As members of the first Greek-letter fraternity for women, today's Thetas uphold a long tradition of leading the way for women's groups and women in higher education.

Learn How to Join Theta

Support Thetas

How do we describe the women who devote time and treasure to Theta? In a word: extraordinary.

Learn How to Support Thetas

Introduce a Potential New Member

Kappa Alpha Theta appreciates the efforts of anyone who recommends outstanding young women for membership.

Introduce a PNM
  • Kristy kurjan 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    Kristi Kurjan

    Beta Pi/Michigan State

    October 2021

    Learn More

  • Anna Guizerix 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    Anna Guizerix

    Epsilon Zeta/Mississippi

    September 2021

    Learn More

  • Anna Richardson 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    Anna Richardson

    Delta Eta/Kansas State

    August 2021

    Learn More

  • 35 Under 35 2021 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    35 Under 35 Recipients

    July 2021

    Learn More

  • Laura Doerre 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    Laura Doerre

    Delta Xi/North Carolina

    June 2021

    Learn More

  • Cheniece Kelleher 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    Cheniece Kelleher

    Gamma Omega/Auburn

    May 2021

    Learn More

  • Lara juras 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    Lara Juras

    Pi/Albion

    April 2021

    Learn More

  • Ann Drake 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    Ann McIlrath Drake

    Beta Omicron/Iowa

    March 2021

    Learn More

  • Lisa Thibault 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    Lisa Thibault

    Epsilon Iota/Westminster

    February 2021

    Learn More

  • Emily Henegar 272x265

    Theta Spotlight

    Each month, Theta recognizes a sister who pursues a passion, makes an impact, and strives to be her best self.

    Emily Henegar

    Eta Phi/Belmont

    January 2021

    Learn More

Notable Thetas

From the very beginning, Theta alumnae have distinguished themselves in their careers and their volunteer endeavors. In fact, some are so well-known that they’re household names, and many have the distinction of being the first women in their professional fields. The archives takes this opportunity to recognize some of our more notable sisters.

View Notable Thetas

Heritage

Are you interested in Theta history or artifacts? Are you a researcher looking into the history of women on college campuses? Explore the story of Theta through our collections, exhibits, articles, and blogs and learn how leading women make history.

Connect to Theta Heritage

Sours: https://www.kappaalphatheta.org/

Kappa reddit

κ-opioid receptor

OPRK1
4DJH bilayer.png
Identifiers
AliasesOPRK1, K-OR-1, KOR, KOR-1, OPRK, opioid receptor kappa 1, KOR1, KOP
External IDsOMIM: 165196MGI: 97439HomoloGene: 20253GeneCards: OPRK1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)Chr 8: 53.23 – 53.25 MbChr 1: 5.59 – 5.61 Mb
PubMed search[3][4]
Wikidata

The κ-opioid receptor or kappa opioid receptor, abbreviated KOR or KOP, is a G protein-coupled receptor that in humans is encoded by the OPRK1gene. The KOR is coupled to the G proteinGi/G0 and is one of four related receptors that bind opioid-like compounds in the brain and are responsible for mediating the effects of these compounds. These effects include altering nociception, consciousness, motor control, and mood. Dysregulation of this receptor system has been implicated in alcohol and drug addiction.[5][6]

The KOR is a type of opioid receptor that binds the opioid peptidedynorphin as the primary endogenous ligand (substrate naturally occurring in the body).[7] In addition to dynorphin, a variety of natural alkaloids, terpenes and synthetic ligands bind to the receptor. The KOR may provide a natural addiction control mechanism, and therefore, drugs that target this receptor may have therapeutic potential in the treatment of addiction.

There is evidence that distribution and/or function of this receptor may differ between sexes.[8][9][10]

Distribution[edit]

KORs are widely distributed in the brain, spinal cord (substantia gelatinosa), and in peripheral tissues. High levels of the receptor have been detected in the prefrontal cortex, periaqueductal gray, raphe nuclei (dorsal), ventral tegmental area, substantia nigra, dorsal striatum (putamen, caudate), ventral striatum (nucleus accumbens, olfactory tubercle), amygdala, bed nucleus stria terminalis, claustrum, hippocampus, hypothalamus, midline thalamic nuclei, locus coeruleus, spinal trigeminal nucleus, parabrachial nucleus, and solitary nucleus.[11][12]

Subtypes[edit]

Based on receptor binding studies, three variants of the KOR designated κ1, κ2, and κ3 have been characterized.[13][14] However, only one cDNA clone has been identified,[15] hence these receptor subtypes likely arise from interaction of one KOR protein with other membrane associated proteins.[16]

All opioid receptors exist as obligate dimers.[citation needed] The implications this may have are not totally known.

Function[edit]

Pain[edit]

Similarly to μ-opioid receptor (MOR) agonists, KOR agonists are potently analgesic, and have been employed clinically in the treatment of pain. However, KOR agonists also produce side effects such as dysphoria, hallucinations, and dissociation, which has limited their clinical usefulness.[17] Examples of KOR agonists that have been used medically as analgesics include butorphanol, nalbuphine, levorphanol, levallorphan, pentazocine, phenazocine, and eptazocine. Difelikefalin (CR845, FE-202845) and CR665 (FE-200665, JNJ-38488502) are peripherally restricted KOR agonists lacking the CNS side effects of centrally active KOR agonists and are currently under clinical investigation as analgesics.

Consciousness[edit]

Centrally active KOR agonists have hallucinogenic or dissociative effects, as exemplified by salvinorin A (the active constituent in Salvia divinorum). These effects are generally undesirable in medicinal drugs. It is thought that the hallucinogenic and dysphoric effects of opioids such as butorphanol, nalbuphine, and pentazocine serve to limit their abuse potential. In the case of salvinorin A, a structurally novel neoclerodanediterpene KOR agonist, these hallucinogenic effects are sought by recreational users, despite the dysphoria experienced by some users. Another KOR agonist with comparable effects is ibogaine, which has possible medical application in addiction treatment. While these KOR agonists possess hallucinogenic and dissociative effects, they are mechanistically and qualitatively different from those of the 5HT2AR agonist psychedelic hallucinogens such as lysergic acid diethylamide (LSD) or psilocybin and those of NMDAR antagonist dissociatives/anesthetics ketamine and phencycldine.[18]

The claustrum is the region of the brain in which the KOR is most densely expressed.[19][20][21] It has been proposed that this area, based on its structure and connectivity, has "a role in coordinating a set of diverse brain functions", and the claustrum has been elucidated as playing a crucial role in consciousness.[20][21] As examples, lesions of the claustrum in humans are associated with disruption of consciousness and cognition, and electrical stimulation of the area between the insula and the claustrum has been found to produce an immediate loss of consciousness in humans along with recovery of consciousness upon cessation of the stimulation.[21][22] On the basis of the preceding knowledge, it has been proposed that inhibition of the claustrum (as well as, "additionally, the deep layers of the cortex, mainly in prefrontal areas") by activation of KORs in these areas is primarily responsible for the profound consciousness-altering/dissociative hallucinogen effects of salvinorin A and other KOR agonists.[20][21] In addition, it has been stated that "the subjective effects of S. divinorum indicate that salvia disrupts certain facets of consciousness much more than the largely serotonergic hallucinogen [LSD]", and it has been postulated that inhibition of a brain area that is apparently as fundamentally involved in consciousness and higher cognitive function as the claustrum may explain this.[20] However, these conclusions are merely tentative, as "[KORs] are not exclusive to the claustrum; there is also a fairly high density of receptors located in the prefrontal cortex, hippocampus, nucleus accumbens and putamen", and "disruptions to other brain regions could also explain the consciousness-altering effects [of salvinorin A]".[21]

In supplementation of the above, according to Addy et al.:[19]

Theories suggest the claustrum may act to bind and integrate multisensory information, or else to encode sensory stimuli as salient or nonsalient (Mathur, 2014). One theory suggests the claustrum harmonizes and coordinates activity in various parts of the cortex, leading to the seamless integrated nature of subjective conscious experience (Crick and Koch, 2005; Stiefel et al., 2014). Disrupting claustral activity may lead to conscious experiences of disintegrated or unusually bound sensory information, perhaps including synesthesia. Such theories are in part corroborated by the fact that [salvia divinorum], which functions almost exclusively on the KOR system, can cause consciousness to be decoupled from external sensory input, leading to experiencing other environments and locations, perceiving other "beings" besides those actually in the room, and forgetting oneself and one's body in the experience.[19]

Mood, stress, and addiction[edit]

See also: κ-opioid receptor § Role in treatment of drug addiction

The involvement of the KOR in stress, as well as in consequences of chronic stress such as depression, anxiety, anhedonia, and increased drug-seeking behavior, has been made clear.[17] KOR agonists are notably dysphoric and aversive at sufficient doses.[23] The KOR antagonists buprenorphine, as ALKS-5461 (a combination formulation with samidorphan), and CERC-501 (LY-2456302) are currently in clinical development for the treatment of major depressive disorder and substance use disorders.[24]JDTic and PF-4455242 were also under investigation but development was halted in both cases due to toxicity concerns.[24]

The depressive-like behaviors following prolonged morphine abstinence appear to be mediated by upregulation of the KOR/dynorphin system in the nucleus accumbens, as the local application of a KOR antagonist prevented the behaviors.[25] As such, KOR antagonists might be useful for the treatment of depressive symptoms associated with opioid withdrawal.[25]

In a small clinical study, pentazocine, a KOR agonist, was found to rapidly and substantially reduce symptoms of mania in patients with bipolar disorder.[8] It was postulated that the efficacy observed was due to KOR activation-mediated amelioration of excessive dopaminergic signaling in the reward pathways.[8][failed verification]

Others[edit]

A variety of other effects of KOR activation are known:

  • Activation of the KOR appears to antagonize many of the effects of the MOR, including analgesia, tolerance, euphoria, and memory regulation.[26]Nalorphine and nalmefene are dual MOR antagonists and KOR agonists that have been used clinically as antidotes for opioid overdose, although the specific role and significance of KOR activation in this indication, if any, is uncertain. In any case however, KOR agonists notably do not affect respiratory drive, and hence do not reverse MOR activation-induced respiratory depression.[27]
  • KOR agonists suppress itching, and the selective KOR agonist nalfurafine is used clinically as an antipruritic (anti-itch drug).
  • Eluxadoline is a peripherally restricted KOR agonist as well as MOR agonist and DOR antagonist that has been approved for the treatment of diarrhea-predominant irritable bowel syndrome. Asimadoline and fedotozine are selective and similarly peripherally restricted KOR agonists that were also investigated for the treatment of irritable bowel syndrome and reportedly demonstrated at least some efficacy for this indication but were ultimately never marketed.
  • KOR agonists are known for their characteristic diuretic effects, due to their negative regulation of vasopressin, also known as antidiuretic hormone (ADH).[28]
  • KOR agonism is neuroprotective against hypoxia/ischemia.[29]
  • The selective KOR agonist U-50488 protected rats against supramaximal electroshockseizures, indicating that KOR agonism may have anticonvulsant effects.[30]

Signal transduction[edit]

KOR activation by agonists is coupled to the G proteinGi/G0, which subsequently increases phosphodiesterase activity. Phosphodiesterases break down cAMP, producing an inhibitory effect in neurons.[31][32][33] KORs also couple to inward-rectifier potassium[34] and to N-type calcium ion channels.[35] Recent studies have also demonstrated that agonist-induced stimulation of the KOR, like other G-protein coupled receptors, can result in the activation of mitogen-activated protein kinases (MAPK). These include extracellular signal-regulated kinase, p38 mitogen-activated protein kinases, and c-Jun N-terminal kinases.[36][37][38][39][40][41]

Ligands[edit]

Agonists[edit]

The synthetic alkaloid ketazocine[42] and terpenoid natural product salvinorin A[18] are potent and selective KOR agonists. The KOR also mediates the dysphoria and hallucinations seen with opioids such as pentazocine.[43]

Nalfurafine (Remitch), which was introduced in 2009, is the first selective KOR agonist to enter clinical use.[50][51]

Antagonists[edit]

  • 5'-Acetamidinoethylnaltrindole (ANTI) – selective [7]
  • 5'-Guanidinonaltrindole (5'-GNTI) – selective, long-acting
  • 6'-Guanidinonaltrindole (6'-GNTI) – biased ligand: G protein agonist, β-arrestin antagonist
  • Amentoflavone – non-selective; naturally-occurring[52]
  • AT-076 – non-selective, likely long acting; JDTic analogue
  • Binaltorphimine – selective, long-acting
  • BU09059 – selective, short-acting; JDTic analogue[53]
  • Buprenorphine – non-selective; silent antagonist or weak partial agonist, depending on source
  • CERC-501 – selective, short-acting
  • Dezocine – non-selective; silent antagonist
  • DIPPA – selective, long-acting [8]
  • JDTic – selective, long-acting
  • LY-255582 - non-selective
  • LY-2459989 – selective, short-acting
  • LY-2795050 – selective, short-acting
  • Methylnaltrexone – non-selective
  • ML190 – selective [9]
  • ML350 – selective, short-acting[53]
  • MR-2266 – non-selective
  • Naloxone – non-selective
  • Naltrexone – non-selective
  • Noribogaine – non-selective; naturally-occurring; biased ligand: G protein agonist, β-arrestin antagonist
  • Norbinaltorphimine – selective, long-acting
  • Pawhuskin A – selective; naturally-occurring[54]
  • PF-4455242 – selective, short-acting
  • Quadazocine – non-selective; silent antagonist; preference for κ2
  • RB-64 (22-thiocyanatosalvinorin A) – G protein biased agonist with a bias factor of 96; β-arrestin antagonist[46]
  • Zyklophin – selective peptide antagonist; dynorphin A analogue

Natural agonists[edit]

Mentha spp.[edit]

Main article: menthol

Found in numerous species of mint, (including peppermint, spearmint, and watermint), the naturally-occurring compound menthol is a weak KOR agonist[55] owing to its antinociceptive, or pain blocking, effects in rats. In addition, mints can desensitize a region through the activation of TRPM8 receptors (the 'cold'/menthol receptor).[56]

Salvia divinorum[edit]

Main article: Salvia divinorum

The key compound in Salvia divinorum, salvinorin A, is known as a powerful, short-acting KOR agonist.[18][57][58]

Ibogaine[edit]

Main article: ibogaine

Used for the treatment of addiction in limited countries, ibogaine has become an icon of addiction management among certain underground circles. Despite its lack of addictive properties, ibogaine is listed as a Schedule I compound in the US because it is a psychoactive substance, hence it is considered illegal to possess under any circumstances. Ibogaine is also a KOR agonist[59] and this property may contribute to the drug's anti-addictive efficacy.

Role in treatment of drug addiction[edit]

KOR agonists had been investigated for their therapeutic potential in the treatment of addiction[60] and evidence points towards dynorphin, the endogenous KOR agonist, to be the body's natural addiction control mechanism.[61] Childhood stress/abuse is a well known predictor of drug abuse and is reflected in alterations of the MOR and KOR systems.[62] In experimental "addiction" models the KOR has also been shown to influence stress-induced relapse to drug seeking behavior. For the drug-dependent individual, risk of relapse is a major obstacle to becoming drug-free. Recent reports demonstrated that KORs are required for stress-induced reinstatement of cocaine seeking.[63][64]

One area of the brain most strongly associated with addiction is the nucleus accumbens (NAcc) and striatum while other structures that project to and from the NAcc also play a critical role. Though many other changes occur, addiction is often characterized by the reduction of dopamine D2 receptors in the NAcc.[65] In addition to low NAcc D2 binding,[66][67] cocaine is also known to produce a variety of changes to the primate brain such as increases prodynorphin mRNA in caudate putamen (striatum) and decreases of the same in the hypothalamus while the administration of a KOR agonist produced an opposite effect causing an increase in D2 receptors in the NAcc.[68]

Additionally, while cocaine overdose victims showed a large increase in KORs (doubled) in the NAcc,[69] KOR agonist administration is shown to be effective in decreasing cocaine seeking and self-administration.[70] Furthermore, while cocaine abuse is associated with lowered prolactin response,[71] KOR activation causes a release in prolactin,[72] a hormone known for its important role in learning, neuronal plasticity and myelination.[73]

It has also been reported that the KOR system is critical for stress-induced drug-seeking. In animal models, stress has been demonstrated to potentiate cocaine reward behavior in a kappa opioid-dependent manner.[74][75] These effects are likely caused by stress-induced drug craving that requires activation of the KOR system. Although seemingly paradoxical, it is well known that drug taking results in a change from homeostasis to allostasis. It has been suggested that withdrawal-induced dysphoria or stress-induced dysphoria may act as a driving force by which the individual seeks alleviation via drug taking.[76] The rewarding properties of drug are altered, and it is clear KOR activation following stress modulates the valence of drug to increase its rewarding properties and cause potentiation of reward behavior, or reinstatement to drug seeking. The stress-induced activation of KORs is likely due to multiple signaling mechanisms. The effects of KOR agonism on dopamine systems are well documented, and recent work also implicates the mitogen-activated protein kinase cascade and pCREB in KOR-dependent behaviors.[39][77]

While the predominant drugs of abuse examined have been cocaine (44%), ethanol (35%), and opioids (24%).[78] As these are different classes of drugs of abuse working through different receptors (increasing dopamine directly and indirectly, respectively) albeit in the same systems produce functionally different responses. Conceptually then pharmacological activation of KOR can have marked effects in any of the psychiatric disorders (depression, bipolar disorder, anxiety, etc.) as well as various neurological disorders (i.e. Parkinson's disease and Huntington's disease).[79][80] Not only are genetic differences in dynorphin receptor expression a marker for alcohol dependence but a single dose of a KOR antagonist markedly increased alcohol consumption in lab animals.[81] There are numerous studies that reflect a reduction in self-administration of alcohol,[82] and heroin dependence has also been shown to be effectively treated with KOR agonism by reducing the immediate rewarding effects[83] and by causing the curative effect of up-regulation (increased production) of MORs[84] that have been down-regulated during opioid abuse.

The anti-rewarding properties of KOR agonists are mediated through both long-term and short-term effects. The immediate effect of KOR agonism leads to reduction of dopamine release in the NAcc during self-administration of cocaine[85] and over the long term up-regulates receptors that have been down-regulated during substance abuse such as the MOR and the D2 receptor. These receptors modulate the release of other neurochemicals such as serotonin in the case of MOR agonists and acetylcholine in the case of D2. These changes can account for the physical and psychological remission of the pathology of addiction. The longer effects of KOR agonism (30 minutes or greater) have been linked to KOR-dependent stress-induced potentiation and reinstatement of drug seeking. It is hypothesized that these behaviors are mediated by KOR-dependent modulation of dopamine, serotonin, or norepinephrine and/or via activation of downstream signal transduction pathways.

Of significant note, while KOR activation blocks many of the behavioral and neurochemical responses elicited by drugs of abuse as stated above. These results are indicative of the KOR induced negative affective states counteracting the rewarding effects of drugs of abuse. Implicating the KOR/dynorphin system as an anti-reward system, supported by the role of KOR signaling and stress, mediating both stress-induced potentiation of drug reward and stress-induced reinstatement of seeking behavior. [79][80] This in turn addresses what was thought to be paradoxical above. That is, rather, KOR signaling is activated/upregulated by stress, drugs of abuse and agonist administration - resulting in negative affective state. As such drug addiction is maintained by avoidance of negative affective states manifest in stress, craving, and drug withdrawal.[86] Consistent with KOR induced negative affective states and role in drug addiction, KOR antagonists are efficacious at blocking negative affect induced by drug withdrawal and at decreasing escalated drug intake in pre-clinical trial involving extended drug access.[79][80][78] Clinically there has been little advancement to evaluate the effects of KOR antagonists due to adverse effects and undesirable pharmacological profiles for clinical testing (i.e. long half-life, poor bioavailability). More recently, a selective, high-affinity KOR antagonist LY2456302 was well-tolerated in CUD patients. [87] Showing feasibility a subsequent proof-of-mechanism trial evaluated JNJ-67953964 (previously LY2456302) potential for treating anhedonia in a double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder. [88] The KOR antagonist significantly increased fMRI ventral striatum activation during reward anticipation while accompanied by therapeutic effects on clinical measures of anhedonia, further reinforces the promise of KOR antagonism and proceeding assessment of clinical impact. [88] Additionally a positron emission tomography (PET) study in cocaine use disorder (CUD) patients utilizing a KOR selective agonist [11C]GR103545 radioligand showed CUD individuals with higher KOR availability were more prone to stress-induced relapse. [89] A subsequent PET scan following a three day cocaine binge showed a decrease in KOR availability, interpreted as increased endogenous dynorphin competing with the radioligand at the KOR binding sites. [89] Taken together these findings are in support of the negative affect state and further implicate the KOR/dynorphin system clinically and therapeutically relevant in humans with CUD. Taken together, in drug addiction the KOR/dynorphin system is implicated as a homeostatic mechanism to counteract the acute effects of drugs of abuse. Chronic drug use and stress up-regulate the system in turn leading to a dysregulated state which induces negative affective states and stress reactivity. [80]

Interactions[edit]

KOR has been shown to interact with sodium-hydrogen antiporter 3 regulator 1,[90][91]ubiquitin C,[92]5-HT1A receptor,[93] and RGS12.[94]

See also[edit]

References[edit]

  1. ^ abcGRCh38: Ensembl release 89: ENSG00000082556 - Ensembl, May 2017
  2. ^ abcGRCm38: Ensembl release 89: ENSMUSG00000025905 - Ensembl, May 2017
  3. ^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^Anderson RI, Becker HC (August 2017). "Role of the Dynorphin/Kappa Opioid Receptor System in the Motivational Effects of Ethanol". Alcoholism, Clinical and Experimental Research. 41 (8): 1402–1418. doi:10.1111/acer.13406. PMC 5522623. PMID 28425121.
  6. ^Karkhanis A, Holleran KM, Jones SR (2017). "Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction". International Review of Neurobiology. 136: 53–88. doi:10.1016/bs.irn.2017.08.001. ISBN . PMID 29056156.
  7. ^James IF, Chavkin C, Goldstein A (1982). "Selectivity of dynorphin for kappa opioid receptors". Life Sciences. 31 (12–13): 1331–4. doi:10.1016/0024-3205(82)90374-5. PMID 6128656.
  8. ^ abcChartoff EH, Mavrikaki M (2015). "Sex Differences in Kappa Opioid Receptor Function and Their Potential Impact on Addiction". Frontiers in Neuroscience. 9: 466. doi:10.3389/fnins.2015.00466. PMC 4679873. PMID 26733781.
  9. ^Rasakham K, Liu-Chen LY (January 2011). "Sex differences in kappa opioid pharmacology". Life Sciences. 88 (1–2): 2–16. doi:10.1016/j.lfs.2010.10.007. PMC 3870184. PMID 20951148.
  10. ^Siciliano CA, Calipari ES, Yorgason JT, Lovinger DM, Mateo Y, Jimenez VA, Helms CM, Grant KA, Jones SR (April 2016). "Increased presynaptic regulation of dopamine neurotransmission in the nucleus accumbens core following chronic ethanol self-administration in female macaques". Psychopharmacology. 233 (8): 1435–43. doi:10.1007/s00213-016-4239-4. PMC 4814331. PMID 26892380.
  11. ^Wang YH, Sun JF, Tao YM, Chi ZQ, Liu JG (September 2010). "The role of kappa-opioid receptor activation in mediating antinociception and addiction". Acta Pharmacologica Sinica. 31 (9): 1065–70. doi:10.1038/aps.2010.138. PMC 4002313. PMID 20729876.
  12. ^Mansour A, Fox CA, Akil H, Watson SJ (January 1995). "Opioid-receptor mRNA expression in the rat CNS: anatomical and functional implications". Trends in Neurosciences. 18 (1): 22–9. doi:10.1016/0166-2236(95)93946-U. PMID 7535487. S2CID 300974.
  13. ^de Costa BR, Rothman RB, Bykov V, Jacobson AE, Rice KC (February 1989). "Selective and enantiospecific acylation of kappa opioid receptors by (1S,2S)-trans-2-isothiocyanato-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexy l] benzeneacetamide. Demonstration of kappa receptor heterogeneity". Journal of Medicinal Chemistry. 32 (2): 281–3. doi:10.1021/jm00122a001. PMID 2536435.
  14. ^Rothman RB, France CP, Bykov V, De Costa BR, Jacobson AE, Woods JH, Rice KC (August 1989). "Pharmacological activities of optically pure enantiomers of the kappa opioid agonist, U50,488, and its cis diastereomer: evidence for three kappa receptor subtypes"(PDF). European Journal of Pharmacology. 167 (3): 345–53. doi:10.1016/0014-2999(89)90443-3. hdl:2027.42/27799. PMID 2553442.
  15. ^Mansson E, Bare L, Yang D (August 1994). "Isolation of a human kappa opioid receptor cDNA from placenta". Biochemical and Biophysical Research Communications. 202 (3): 1431–7. doi:10.1006/bbrc.1994.2091. PMID 8060324.
  16. ^Jordan BA, Devi LA (June 1999). "G-protein-coupled receptor heterodimerization modulates receptor function". Nature. 399 (6737): 697–700. Bibcode:1999Natur.399..697J. doi:10.1038/21441. PMC 3125690. PMID 10385123.
  17. ^ abLand BB, Bruchas MR, Lemos JC, Xu M, Melief EJ, Chavkin C (January 2008). "The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system". The Journal of Neuroscience. 28 (2): 407–14. doi:10.1523/JNEUROSCI.4458-07.2008. PMC 2612708. PMID 18184783.
  18. ^ abcRoth BL, Baner K, Westkaemper R, Siebert D, Rice KC, Steinberg S, Ernsberger P, Rothman RB (September 2002). "Salvinorin A: a potent naturally occurring nonnitrogenous kappa opioid selective agonist". Proceedings of the National Academy of Sciences of the United States of America. 99 (18): 11934–9. Bibcode:2002PNAS...9911934R. doi:10.1073/pnas.182234399. PMC 129372. PMID 12192085.
  19. ^ abcAddy PH, Garcia-Romeu A, Metzger M, Wade J (April 2015). "The subjective experience of acute, experimentally-induced Salvia divinorum inebriation". Journal of Psychopharmacology. 29 (4): 426–35. doi:10.1177/0269881115570081. PMID 25691501. S2CID 34171297.
  20. ^ abcdStiefel KM, Merrifield A, Holcombe AO (2014). "The claustrum's proposed role in consciousness is supported by the effect and target localization of Salvia divinorum". Frontiers in Integrative Neuroscience. 8: 20. doi:10.3389/fnint.2014.00020. PMC 3935397. PMID 24624064.
  21. ^ abcdeChau A, Salazar AM, Krueger F, Cristofori I, Grafman J (November 2015). "The effect of claustrum lesions on human consciousness and recovery of function". Consciousness and Cognition. 36: 256–64. doi:10.1016/j.concog.2015.06.017. PMID 26186439. S2CID 46139982.
  22. ^Koubeissi MZ, Bartolomei F, Beltagy A, Picard F (August 2014). "Electrical stimulation of a small brain area reversibly disrupts consciousness". Epilepsy & Behavior. 37: 32–5. doi:10.1016/j.yebeh.2014.05.027. PMID 24967698. S2CID 8368944.
  23. ^Xuei X, Dick D, Flury-Wetherill L, Tian HJ, Agrawal A, Bierut L, Goate A, Bucholz K, Schuckit M, Nurnberger J, Tischfield J, Kuperman S, Porjesz B, Begleiter H, Foroud T, Edenberg HJ (November 2006). "Association of the kappa-opioid system with alcohol dependence". Molecular Psychiatry. 11 (11): 1016–24. doi:10.1038/sj.mp.4001882. PMID 16924269.
  24. ^ abUrbano M, Guerrero M, Rosen H, Roberts E (May 2014). "Antagonists of the kappa opioid receptor". Bioorganic & Medicinal Chemistry Letters. 24 (9): 2021–32. doi:10.1016/j.bmcl.2014.03.040. PMID 24690494.
  25. ^ abZan GY, Wang Q, Wang YJ, Liu Y, Hang A, Shu XH, Liu JG (September 2015). "Antagonism of κ opioid receptor in the nucleus accumbens prevents the depressive-like behaviors following prolonged morphine abstinence". Behavioural Brain Research. 291: 334–41. doi:10.1016/j.bbr.2015.05.053. PMID 26049060. S2CID 32817749.
  26. ^Pan ZZ (March 1998). "mu-Opposing actions of the kappa-opioid receptor". Trends in Pharmacological Sciences. 19 (3): 94–8. doi:10.1016/S0165-6147(98)01169-9. PMID 9584625.
  27. ^Kaye AD, Vadivelu N, Urman RD (1 December 2014). Substance Abuse: Inpatient and Outpatient Management for Every Clinician. Springer. pp. 181–. ISBN .
  28. ^Yamada K, Imai M, Yoshida S (January 1989). "Mechanism of diuretic action of U-62,066E, a kappa opioid receptor agonist". European Journal of Pharmacology. 160 (2): 229–37. doi:10.1016/0014-2999(89)90495-0. PMID 2547626.
  29. ^Zeynalov E, Nemoto M, Hurn PD, Koehler RC, Bhardwaj A (March 2006). "Neuroprotective effect of selective kappa opioid receptor agonist is gender specific and linked to reduced neuronal nitric oxide". Journal of Cerebral Blood Flow and Metabolism. 26 (3): 414–20. doi:10.1038/sj.jcbfm.9600196. PMID 16049424.
  30. ^Tortella FC, Robles L, Holaday JW (April 1986). "U50,488, a highly selective kappa opioid: anticonvulsant profile in rats". The Journal of Pharmacology and Experimental Therapeutics. 237 (1): 49–53. PMID 3007743.
  31. ^Lawrence DM, Bidlack JM (September 1993). "The kappa opioid receptor expressed on the mouse R1.1 thymoma cell line is coupled to adenylyl cyclase through a pertussis toxin-sensitive guanine nucleotide-binding regulatory protein". The Journal of Pharmacology and Experimental Therapeutics. 266 (3): 1678–83. PMID 8103800.
  32. ^Konkoy CS, Childers SR (January 1993). "Relationship between kappa 1 opioid receptor binding and inhibition of adenylyl cyclase in guinea pig brain membranes". Biochemical Pharmacology. 45 (1): 207–16. doi:10.1016/0006-2952(93)90394-C. PMID 8381004.
  33. ^Schoffelmeer AN, Rice KC, Jacobson AE, Van Gelderen JG, Hogenboom F, Heijna MH, Mulder AH (September 1988). "Mu-, delta- and kappa-opioid receptor-mediated inhibition of neurotransmitter release and adenylate cyclase activity in rat brain slices: studies with fentanyl isothiocyanate". European Journal of Pharmacology. 154 (2): 169–78. doi:10.1016/0014-2999(88)90094-5. PMID 2906610.
  34. ^Henry DJ, Grandy DK, Lester HA, Davidson N, Chavkin C (March 1995). "Kappa-opioid receptors couple to inwardly rectifying potassium channels when coexpressed by Xenopus oocytes". Molecular Pharmacology. 47 (3): 551–7. PMID 7700253.
  35. ^Tallent M, Dichter MA, Bell GI, Reisine T (December 1994). "The cloned kappa opioid receptor couples to an N-type calcium current in undifferentiated PC-12 cells". Neuroscience. 63 (4): 1033–40. doi:10.1016/0306-4522(94)90570-3. PMID 7700508. S2CID 22003522.
  36. ^Bohn LM, Belcheva MM, Coscia CJ (February 2000). "Mitogenic signaling via endogenous kappa-opioid receptors in C6 glioma cells: evidence for the involvement of protein kinase C and the mitogen-activated protein kinase signaling cascade". Journal of Neurochemistry. 74 (2): 564–73. doi:10.1046/j.1471-4159.2000.740564.x. PMC 2504523. PMID 10646507.
  37. ^Belcheva MM, Clark AL, Haas PD, Serna JS, Hahn JW, Kiss A, Coscia CJ (July 2005). "Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in astrocytes". The Journal of Biological Chemistry. 280 (30): 27662–9. doi:10.1074/jbc.M502593200. PMC 1400585. PMID 15944153.
  38. ^Bruchas MR, Macey TA, Lowe JD, Chavkin C (June 2006). "Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes". The Journal of Biological Chemistry. 281 (26): 18081–9. doi:10.1074/jbc.M513640200. PMC 2096730. PMID 16648139.
  39. ^ abBruchas MR, Xu M, Chavkin C (September 2008). "Repeated swim stress induces kappa opioid-mediated activation of extracellular signal-regulated kinase 1/2". NeuroReport. 19 (14): 1417–22. doi:10.1097/WNR.0b013e32830dd655. PMC 2641011. PMID 18766023.
  40. ^Kam AY, Chan AS, Wong YH (July 2004). "Kappa-opioid receptor signals through Src and focal adhesion kinase to stimulate c-Jun N-terminal kinases in transfected COS-7 cells and human monocytic THP-1 cells". The Journal of Pharmacology and Experimental Therapeutics. 310 (1): 301–10. doi:10.1124/jpet.104.065078. PMID 14996948. S2CID 39445016.
  41. ^Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, Chavkin C (October 2007). "Long-acting kappa opioid antagonists disrupt receptor signaling and produce noncompetitive effects by activating c-Jun N-terminal kinase". The Journal of Biological Chemistry. 282 (41): 29803–11. doi:10.1074/jbc.M705540200. PMC 2096775. PMID 17702750.
  42. ^Pasternak GW (June 1980). "Multiple opiate receptors: [3H]ethylketocyclazocine receptor binding and ketocyclazocine analgesia". Proceedings of the National Academy of Sciences of the United States of America. 77 (6): 3691–4. Bibcode:1980PNAS...77.3691P. doi:10.1073/pnas.77.6.3691. PMC 349684. PMID 6251477.
  43. ^Holtzman SG (February 1985). "Drug discrimination studies". Drug and Alcohol Dependence. 14 (3–4): 263–82. doi:10.1016/0376-8716(85)90061-4. PMID 2859972.
  44. ^Nielsen CK, Ross FB, Lotfipour S, Saini KS, Edwards SR, Smith MT (December 2007). "Oxycodone and morphine have distinctly different pharmacological profiles: radioligand binding and behavioural studies in two rat models of neuropathic pain". Pain. 132 (3): 289–300. doi:10.1016/j.pain.2007.03.022. PMID 17467904. S2CID 19872213.
  45. ^Gupta A, Gomes I, Bobeck EN, Fakira AK, Massaro NP, Sharma I, Cavé A, Hamm HE, Parello J, Devi LA (2016). "Collybolide is a novel biased agonist of κ-opioid receptors with potent antipruritic activity". Proc. Natl. Acad. Sci. U.S.A. 113 (21): 6041–6. Bibcode:2016PNAS..113.6041G. doi:10.1073/pnas.1521825113. PMC 4889365. PMID 27162327.
  46. ^ abWhite KL, Robinson JE, Zhu H, DiBerto JF, Polepally PR, Zjawiony JK, Nichols DE, Malanga CJ, Roth BL (January 2015). "The G protein-biased κ-opioid receptor agonist RB-64 is analgesic with a unique spectrum of activities in vivo". The Journal of Pharmacology and Experimental Therapeutics. 352 (1): 98–109. doi:10.1124/jpet.114.216820. PMC 4279099. PMID 25320048.
  47. ^Wang Y, Chen Y, Xu W, Lee DY, Ma Z, Rawls SM, Cowan A, Liu-Chen LY (March 2008). "2-Methoxymethyl-salvinorin B is a potent kappa opioid receptor agonist with longer lasting action in vivo than salvinorin A". The Journal of Pharmacology and Experimental Therapeutics. 324 (3): 1073–83. doi:10.1124/jpet.107.132142. PMC 2519046. PMID 18089845.
  48. ^Munro TA, Duncan KK, Xu W, Wang Y, Liu-Chen LY, Carlezon WA, Cohen BM, Béguin C (February 2008). "Standard protecting groups create potent and selective kappa opioids: salvinorin B alkoxymethyl ethers". Bioorganic & Medicinal Chemistry. 16 (3): 1279–86. doi:10.1016/j.bmc.2007.10.067. PMC 2568987. PMID 17981041.
  49. ^Baker LE, Panos JJ, Killinger BA, Peet MM, Bell LM, Haliw LA, Walker SL (April 2009). "Comparison of the discriminative stimulus effects of salvinorin A and its derivatives to U69,593 and U50,488 in rats". Psychopharmacology. 203 (2): 203–11. doi:10.1007/s00213-008-1458-3. PMID 19153716.
  50. ^Graham L. Patrick (10 January 2013). An Introduction to Medicinal Chemistry. OUP Oxford. pp. 657–. ISBN .
  51. ^Nagase H (21 January 2011). Chemistry of Opioids. Springer. pp. 34, 48, 57–60. ISBN .
  52. ^Katavic PL, Lamb K, Navarro H, Prisinzano TE (August 2007). "Flavonoids as opioid receptor ligands: identification and preliminary structure-activity relationships". Journal of Natural Products. 70 (8): 1278–82. doi:10.1021/np070194x. PMC 2265593. PMID 17685652.
  53. ^ abCasal-Dominguez JJ, Furkert D, Ostovar M, Teintang L, Clark MJ, Traynor JR, Husbands SM, Bailey SJ (March 2014). "Characterization of BU09059: a novel potent selective κ-receptor antagonist". ACS Chemical Neuroscience. 5 (3): 177–84. doi:10.1021/cn4001507. PMC 3963132. PMID 24410326.
  54. ^Hartung AM, Beutler JA, Navarro HA, Wiemer DF, Neighbors JD (February 2014). "Stilbenes as κ-selective, non-nitrogenous opioid receptor antagonists". Journal of Natural Products. 77 (2): 311–9. doi:10.1021/np4009046. PMC 3993902. PMID 24456556.
  55. ^Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A, Ghelardini C (April 2002). "Menthol: a natural analgesic compound". Neuroscience Letters. 322 (3): 145–8. doi:10.1016/S0304-3940(01)02527-7. PMID 11897159. S2CID 33979563.
  56. ^Werkheiser JL, Rawls SM, Cowan A (October 2006). "Mu and kappa opioid receptor agonists antagonize icilin-induced wet-dog shaking in rats". European Journal of Pharmacology. 547 (1–3): 101–5. doi:10.1016/j.ejphar.2006.07.026. PMID 16945367.
  57. ^Butelman ER, Mandau M, Tidgewell K, Prisinzano TE, Yuferov V, Kreek MJ (January 2007). "Effects of salvinorin A, a kappa-opioid hallucinogen, on a neuroendocrine biomarker assay in nonhuman primates with high kappa-receptor homology to humans"(PDF). The Journal of Pharmacology and Experimental Therapeutics. 320 (1): 300–6. doi
Sours: https://en.wikipedia.org/wiki/%CE%9A-opioid_receptor

Sign in

r/kappa (Reddit Kappa) is a "Fighting Game Community Hub" and I use the term lightly. This so called "Hub" has absolutely nothing to do with the growth, evolution, and the progression of the Fighting Game Community. The site serves absolutely no purpose but for trolls to spam the following: gore, porn, trollposts, multiple alt accounts, brigading, stalking, harassing other redditors & undermining and bashing casual fighting game fans. As the age of E-Sports is upon us all, this subreddit serves no purpose, and only holds the Fighting Game Community back.

There is also an "Exclusive" community within r/kappa, where the moderators use the app, Slack Chat. Within this Slack Chat, these so called "elite" members, create alt accounts to play GOD within the subreddit and create / decide what goes on. Think of these people as r/kappa 's own Bootleg Illuminati. They claim to "Sponsor" players, but only for their own personal gain.

The Fighting Game Community will never be marketable for E-Sport Companies / Leagues until garbage like r/kappa dies out. Please sign and support the growth of the FGC, by removing this subreddit from existence.

Share for Success

116

Signatures

Sours: https://www.ipetitions.com/petition/petition-to-remove-the-rkappa-subreddit

Now discussing:

I was dumbfounded. No, I'm not an angel either, I had women on trips. But somehow I could not even imagine that when I was fucking some slut, at this very time, some freak was. Fucking my wife.



590 591 592 593 594