[18] Examples of KOR agonists that have been used medically as analgesics include butorphanol, nalbuphine, levorphanol, levallorphan, pentazocine, phenazocine, and eptazocine.

It is thought that the hallucinogenic and dysphoric effects of opioids such as butorphanol, nalbuphine, and pentazocine serve to limit their abuse potential.

[21] 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]".

[22] In supplementation of the above, according to Addy et al.:[20] 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.

[26] 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.

[36] 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).

[50][51] Found in numerous species of mint, (including peppermint, spearmint, and watermint), the naturally-occurring compound menthol is a weak KOR agonist[56] owing to its antinociceptive, or pain blocking, effects in rats.

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.

[69] In addition to low NAcc D2 binding,[70][71] 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.

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.

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.

[92] 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.

[93][94] Studies in humans same to similar conclusions that KORs may modulate various aspects of reward processing in a manner that is independent of the hedonic valence traditionally ascribed to them.

[95][96] This broadens the potential understanding of KORs in addiction beyond a unidimensional framework, implicating their role in complex behaviors and treatment approaches that do not align strictly with stress or aversion.

These emerging perspectives may inform the development of novel pharmacotherapies targeting KORs for the treatment of substance use disorders, as they highlight the receptor's multifaceted role in addiction.