ABSTRACT The κ-opioid receptor (KOR), a member of the opioid receptor family, is widely expressed in the central nervous system and peripheral tissues. Substantial evidence has shown that

activation of KOR by agonists and endogenous opioid peptides _in vivo_ may produce a strong analgesic effect that is free from the abuse potential and the adverse side effects of μ-opioid

receptor (MOR) agonists, such as morphine. In addition, activation of the KOR has also been shown to exert an inverse effect on morphine-induced adverse actions, such as tolerance, reward,

and impairment of learning and memory. Therefore, the KOR has received much attention in the effort to develop alternative analgesics to MOR agonists and agents for the treatment of drug

therapeutic application of κ-agonists in the treatment of pain and drug addiction is also discussed. SIMILAR CONTENT BEING VIEWED BY OTHERS EFFECTS OF THE NOVEL SELECTIVE Κ-OPIOID RECEPTOR

AGONIST NP-5497-KA ON MORPHINE-INDUCED REWARD-RELATED BEHAVIORS Article Open access 24 October 2023 NOVEL SELECTIVE Κ AGONISTS SLL-039 AND SLL-1206 PRODUCE POTENT ANTINOCICEPTION WITH FEWER

SEDATION AND AVERSION Article 07 September 2021 SYSTEMIC KAPPA OPIOID RECEPTOR ANTAGONISM ACCELERATES REINFORCEMENT LEARNING VIA AUGMENTATION OF NOVELTY PROCESSING IN MALE MICE Article Open

access 17 February 2023 INTRODUCTION Pharmacological studies have established the existence of two types of κ-opioid receptor (KOR). One subtype of KOR, κ1, binds U69593 with a high

affinity, whereas the κ2 subtype binds this drug with a low affinity1. A naloxone benzoylhydrazone sensitive KOR subtype (κ3) has also been proposed but not been fully confirmed by

sufficient evidence2, 3, 4. So far only KOR1 has been cloned in human and rodents4, 5. KORs are coupled to heterotrimer Gi/o proteins. Activation of KORs leads to an inhibition of adenylyl

cyclase through the Gα subunit and induces increased potassium channel conductance and decreased calcium conductance via the Gβγ subunit6. Modulation of these ion channels by KORs in neurons

results in decreased action potential generation and neurotransmitter release. Stimulation of KORs has also been shown to activate ERK (extracellular regulated kinase), JNK (c-Jun

N-terminal kinase), and p38 MAPK (mitogen-activated protein kinase) signal transduction cascades7, 8, 9, 10, 11, 12, 13. Additionally, there is evidence that activation of KORs stimulates

Na-H exchanger-3 activity via Na+-H+-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50, independent of pertussis toxin-sensitive G proteins14. After repeated or

sustained exposure to agonists, KORs are desensitized by receptor phosphorylation and recruitment of β-arrestin and endocytosed via a clathrin-and dynamin-dependent pathway. These

internalized receptors either return to the membrane by dephosphorylation and EBP50/NHERF-1-dependent recycling or are degraded via both lysosome and proteasome systems15, 16. G-protein

receptor kinase 3 (GRK3) and β-arrestin 1/2 play important roles in the modulation of KOR trafficking12, 17. KORs are widely expressed throughout the brain, spinal cord, and peripheral

tissues7. High levels of KOR mRNA have been detected in the ventral tegmental area (VTA), nucleus accumbens (NAc), prefrontal cortex (PFC), hippocampus, striatum, amygdala, locus coeruleus

(LC), substantia nigra (SN), dorsal raphe nucleus (DRN) and hypothalamus of both the rat and human brains5, 18, 19, 20. These brain areas are implicated in the modulation of reward, mood

state and cognitive function. KORs are also expressed at several levels of pain circuitry, including areas such as the dorsal root ganglia, dorsal spinal cord, rostral ventromedial medulla,

periaqueductal gray (PAG), sensory thalamus and the limbic regions12, 21, 22, 23. Activation of KORs _in vivo_ produces many effects including analgesia, dysphoria, water diuresis,

corticosteroid elevations, immunomodulation, decreases in pilocarpine-induced seizure and associated mossy fiber sprouting and hilar neuron loss16. KOR agonists have attracted considerable

attention for their ability to exert potent analgesic effects without high abuse potential24, 25, 26, 27 and antagonize various MOR-mediated actions in the brain, including analgesia,

tolerance, reward and memory processes28. THE ROLE OF THE Κ-OPIOID SYSTEM IN THE MODULATION OF ANTINOCICEPTION AND DRUG ADDICTION The κ-opioid system consists of the dynorphin family of

neuropeptides and KORs29, 30. Dynorphins (Dyns) are composed of seven peptides of varying lengths that are formed from the precursor prodynorphin (PDyn; see Schwarzer, 200931). They are

released from the presynaptic terminal of depolarized PDyn-containing neurons following sequential enzymatic cleavage, mainly by proprotein convertase-232, 33. The Dyn/KOR system can mediate

antinociception and drug reward through presynaptic and postsynaptic modulation of the levels of several neurotransmitters such as dopamine (DA), γ-Aminobutyric acid (GABA) and glutamate19,

34. It has been well established that the Dyn/KOR system exerts an inhibitory effect on brain reward function by suppressing DA release from the mesolimbic reward pathway and the

nigrostriatal pathway4, 35, 36, 37, 38. These brain regions are intimately associated with the development of drug dependence. Numerous studies in both nonhuman primates and rats have

demonstrated that κ-agonists functionally attenuate many behavioral effects of cocaine, including behavioral sensitization39, 40 place preference40, 41, 42, and self-administration43, 44,

45, 46. Administration of κ-agonists also attenuates the reinstatement of extinguished drug-taking behavior in an animal model of relapse46, 47. These inhibitory effects of κ-agonists on

cocaine-induced abuse-related behaviors are possibly achieved by inhibiting the release of DA from dopaminergic neurons37, 48. A role for KORs in pain circuits has been widely described in

both the central and peripheral nervous systems. Although it has been reported that KOR activation antagonizes MOR-mediated analgesia, numerous studies have documented potent antinociceptive

effects after intrathecal and systemic administration of selective κ-agonists49, 50, 51, 52. Moreover, κ-opioid agonists are free from the abuse potential and adverse side effects of

μ-agonists such as morphine24, 25, 26, 27. Additionally, pharmacologic studies in KOR and PDyn knockout mice indicate important roles for KORs in mediating inhibition of visceral, chemical,

inflammatory and thermal pain12, 53, 54. Peripherally selective κ-agonists (including the peptide κ-agonists55) act as particularly potent analgesics after systemic administration in a wide

variety of visceral-pain and inflammatory-pain models as well as in thermal hyperalgesia induced by capsaicin. Moreover, the analgesic potency of κ-agonists is enhanced under inflammatory

conditions56, 57, 58, 59, 60, 61. Both central and peripheral sites of action may contribute to these endpoints62, 63, 64. THE ROLE OF THE Κ-OPIOID SYSTEM IN MODULATION OF THE AVERSIVE

EFFECTS OF STRESS AND DRUG RELAPSE Although accumulating evidence demonstrates that KOR agonists produce potent analgesic effects and suppress drug reward, these agonists have also been

shown to produce aversive mood and facilitate drug relapse7. For example, KOR activation produces dysphoria (defined here as an unpleasant or aversive state) in humans65, 66 and

pro-depression-like behaviors (_eg_, anhedonia, dysphoria, and anxiety) in rodents67, 68, 69, 70. Moreover, the aversive effects of KOR agonists have also been characterized extensively in

rodents using place conditioning paradigms, where they establish conditioned place aversions (CPAs) after systemic administration30, 41, 71, 72, 73 or microinfusion into the

mesocorticolimbic DA system67, 74. In addition, stimulation of KORs with selective agonist can cause a Dyn/KOR-dependent reinstatement of extinguished cocaine CPP (conditioned place

preference) or drug self-administration75, 76, 77, 78. These reports suggest that activation of the Dyn/KOR system is likely to play a major role in stress-induced reinstatement and that

blockade of KOR receptors with selective antagonists may be a useful and powerful therapeutic strategy for protecting individuals from relapse to drug abuse. Furthermore, the fact that KOR

function appears to have a profound influence on behaviors that are thought to reflect motivational and emotional states in animal models suggests that KORs might represent a viable target

for psychiatric medications. An application of KOR antagonists is in the treatment of depressive and anxiety-related disorders, both of which are triggered or exacerbated by stress12.

POTENTIAL THERAPEUTIC APPLICATIONS OF Κ-OPIOID AGONISTS IN PAIN RELIEF AND DRUG ADDICTION TREATMENT POTENTIAL THERAPEUTIC APPLICATIONS IN PAIN RELIEF Although MOR agonists are still regarded

as the gold standard to relieve severe pain, their therapeutic utility is limited by the tendency to cause addiction following repeated or prolonged administration. Because KOR agonists can

exert potent analgesic effects and suppress the drug reward response, they were initially expected to be used as non-addictive analgesics. However, in clinical trials51, 56, selective

κ-agonists that freely enter the central nervous system (_eg_, ICI199441, enadoline, and spiradoline) have been shown to produce unpleasant central side effects, such as dysphoria, sedation

and diuresis. As a result, there has been an attempt to develop peripherally selective κ-agonists51 and mixed κ/μ-agonists79, 80, 81 in the hopes of developing strong analgesics devoid of

central side effects. Synthetic κ-agonists, as well as Dyn A, have been reported to reduce morphine tolerance in a variety of antinociceptive tests80, 82, 83. Although the endogenous Dyns,

Dyn A analogs (_eg_, E2078) and other peptide κ-agonists (_eg_, CR665 and CR845) have several advantages such as high activity, high specificity and low toxicity, the delivery of peptides as

therapeutic agents remains a challenge due to their metabolic instability55. Currently, peripherally selective κ-agonists (including the peptide κ-agonists55) are under development as new

analgesics due to their lack of central side effects such as respiratory depression, nausea, sedation, dysphoria, addiction and analgesic tolerance51, 56. Nevertheless, none have thus far

been approved for use as analgesics. The popular analgesics available today are still classical compounds with mixed κ- and μ-activity such as pentazocine, butorphanol and nalbuphine81.

Cyclazocine and morphinan derivatives are novel κ-agonists with additional μ-activity, which have attracted much recent attention for their ability to inhibit antinociceptive tolerance and

cocaine-reinforced responding with fewer undesirable side effects79, 80. POTENTIAL THERAPEUTIC APPLICATIONS IN THE TREATMENT OF DRUG ADDICTION Drug addiction is a disorder characterized by

chronic relapse, which is accompanied by the compulsion to seek and take the drug, loss of control in limiting intake and emergence of a negative emotional state (_eg_, dysphoria, anxiety,

irritability) when access to the drug is prevented84. The addiction cycle is composed of three stages: binge/intoxication, withdrawal/negative affect and preoccupation/anticipation.

Additionally, the withdrawal symptoms after removal of chronic drug administration include signs of physical dependence and negative emotional state (dysphoria, anxiety and irritability)84.

It has been demonstrated that κ-agonists can attenuate opiate withdrawal symptoms both in opiate-dependent animals and in humans28, 53, 55, 82, 85, 86, 87. This attenuation may be due to

κ-agonists possibly preventing drug withdrawal by inhibiting glutamatergic, GABAergic, or noradrenergic transmission in brain sites that mediate negative mood states such as the central

nucleus of the amygdala (CeA) or bed nucleus of the stria terminalis (BNST)4. A wealth of studies indicates that κ-agonists can antagonize cocaine-induced alterations in behavior and brain

chemistry34, 88. Several studies have demonstrated that κ-agonists are effective at decreasing the rate of cocaine self-administration both in humans and in animal models43, 46, 47, 89, 90.

Also, κ-agonists attenuate the development and long-term expression of cocaine-induced behavioral sensitization following their repeated, intermittent administration91. These effects most

likely result from the inhibition of limbic DA release after acute administration of κ-agonists34, 88, 92, 93. However, there is paradoxical evidence that continuous or prior exposure to

κ-agonists can potentiate the rewarding effects of cocaine under stress conditions and stress-induced reinstatement36, 94, 95. This evidence suggests that selective antagonists of KOR may

represent useful and powerful therapeutic treatments for protecting individuals from relapse to drug abuse. A growing number of preclinical studies have demonstrated that nonselective

κ-agonists with additional activity at MORs can decrease cocaine self-administration with fewer side effects than highly selective κ-agonists44, 79, 80, 96, 97, 98, indicating that

mixed-action κ/μ-agonists may have particular utility for the treatment of drug abuse. Taken together, the majority of these findings indicate that κ-agonists antagonize both the behavioral

and neurochemical effects of cocaine. The administration of κ-agonists can functionally attenuate behavioral effects of cocaine, including CPP, self-administration and behavioral

sensitization. These inhibitory effects of κ-agonists on abuse-related behaviors are possibly achieved by suppressing DA release. Additionally, compounds with mixed κ- and μ-activity may be

more promising candidate pharmacotherapies for drug abuse than selective κ-agonists. However, there is evidence that KOR agonists produce aversive mood and facilitate drug relapse.

Therefore, further studies are needed to confirm the utility of κ-agonists in the treatment of substance abuse. CONCLUSIONS AND THERAPEUTIC PERSPECTIVES Data from cell culture, experimental

animals and humans have provided cellular, neurochemical, and behavioral evidence that KOR activity plays a key role in mediating antinociception, drug withdrawal symptoms and cocaine reward

responses. Thus, κ-agonists are likely to become analgesics or even anti-addiction drugs without tolerance and dependence development following chronic drug exposure. Moreover, for the

peripherally selective κ-agonists, their ability to exert potent analgesic effects in a variety of visceral pain conditions without presenting central side effects suggest a bright drug

development future. Additionally, mixed-action κ-/μ-agonists may have promising uses for the treatment of pain or drug abuse with few side effects. However, all these predicted therapeutic

applications require further study. REFERENCES * Zukin RS, Eghbali M, Olive D, Unterwald EM, Tempel A . Characterization and visualization of rat and guinea pig brain kappa opioid receptors:

evidence for kappa 1 and kappa 2 opioid receptors. _Proc Natl Acad Sci USA_ 1988; 85: 4061–5. Article  CAS  PubMed  PubMed Central  Google Scholar  * Clark JA, Liu L, Price M, Hersh B,

Edelson M, Pasternak GW . Kappa opiate receptor multiplicity: evidence for two U50,488-sensitive kappa 1 subtypes and a novel kappa 3 subtype. _J Pharmacol Exp Ther_ 1989; 251: 461–8. CAS 

PubMed  Google Scholar  * Connor M, Kitchen I . Has the sun set on kappa3-opioid receptors? _Br J Pharmacol_ 2006; 147: 349–50. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Bruijnzeel AW . kappa-Opioid receptor signaling and brain reward function. _Brain Res Rev_ 2009; 62: 127–46. Article  CAS  PubMed  PubMed Central  Google Scholar  * Simonin F, Gaveriaux-Ruff

C, Befort K, Matthes H, Lannes B, Micheletti G, _et al_. kappa-Opioid receptor in humans: cDNA and genomic cloning, chromosomal assignment, functional expression, pharmacology, and

expression pattern in the central nervous system. _Proc Natl Acad Sci USA_ 1995; 92: 7006–10. Article  CAS  PubMed  PubMed Central  Google Scholar  * Dhawan BN, Cesselin F, Raghubir R,

Reisine T, Bradley PB, Portoghese PS, _et al_. International Union of Pharmacology. XII. Classification of opioid receptors. _Pharmacol Rev_ 1996; 48: 567–92. CAS  PubMed  Google Scholar  *

Bruchas MR, Land BB, Chavkin C . The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. _Brain Res_ 2010; 1314: 44–55. Article  CAS  PubMed  Google

Scholar  * Bruchas MR, Macey TA, Lowe JD, Chavkin C . Kappa opioid receptor activation of p38 MAPK is GRK3- and arrestin-dependent in neurons and astrocytes. _J Biol Chem_ 2006; 281:

18081–9. Article  CAS  PubMed  Google Scholar  * Bruchas MR, Yang T, Schreiber S, Defino M, Kwan SC, Li S, _et al_. Long-acting kappa opioid antagonists disrupt receptor signaling and

produce noncompetitive effects by activating c-Jun N-terminal kinase. _J Biol Chem_ 2007; 282: 29803–11. Article  CAS  PubMed  Google Scholar  * McLennan GP, Kiss A, Miyatake M, Belcheva MM,

Chambers KT, Pozek JJ, _et al_. Kappa opioids promote the proliferation of astrocytes via Gbetagamma and beta-arrestin 2-dependent MAPK-mediated pathways. _J neurochem_ 2008; 107: 1753–65.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Camilleri M . Novel pharmacology: asimadoline, a kappa-opioid agonist, and visceral sensation. _Neurogastroenterol Motil_ 2008; 20:

971–9. Article  CAS  PubMed  PubMed Central  Google Scholar  * Knoll AT, Carlezon Jr . Dynorphin, stress, and depression. _Brain Res_ 2010; 1314: 56–73. Article  CAS  PubMed  Google Scholar

  * Belcheva MM, Clark AL, Haas PD, Serna JS, Hahn JW, Kiss A, _et al_. Mu and kappa opioid receptors activate ERK/MAPK via different protein kinase C isoforms and secondary messengers in

astrocytes. _J Biol Chem_ 2005; 280: 27662–9. Article  CAS  PubMed  Google Scholar  * Huang P, Steplock D, Weinman EJ, Hall RA, Ding Z, Li J, _et al_. kappa Opioid receptor interacts with

Na(+)/H(+)-exchanger regulatory factor-1/Ezrin-radixin-moesin-binding phosphoprotein-50 (NHERF-1/EBP50) to stimulate Na(+)/H(+) exchange independent of G(i)/G(o) proteins. _J Biol Chem_

2004; 279: 25002–9. Article  CAS  PubMed  Google Scholar  * Chen Y, Chen C, Liu-Chen LY . Dynorphin peptides differentially regulate the human kappa opioid receptor. _Life Sci_ 2007; 80:

1439–48. Article  CAS  PubMed  PubMed Central  Google Scholar  * Liu-Chen LY . Agonist-induced regulation and trafficking of kappa opioid receptors. _Life Sci_ 2004; 75: 511–36. Article  CAS

  PubMed  Google Scholar  * McLaughlin JP, Myers LC, Zarek PE, Caron MG, Lefkowitz RJ, Czyzyk TA, _et al_. Prolonged kappa opioid receptor phosphorylation mediated by G-protein receptor

kinase underlies sustained analgesic tolerance. _J Biol Chem_ 2004; 279: 1810–8. Article  CAS  PubMed  Google Scholar  * Meng F, Xie GX, Thompson RC, Mansour A, Goldstein A, Watson SJ, _et

al_. Cloning and pharmacological characterization of a rat kappa opioid receptor. _Proc Natl Acad Sci USA_ 1993; 90: 9954–8. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kreibich

A, Reyes BA, Curtis AL, Ecke L, Chavkin C, Van Bockstaele EJ, _et al_. Presynaptic inhibition of diverse afferents to the locus ceruleus by kappa-opiate receptors: a novel mechanism for

regulating the central norepinephrine system. _J Neurosci_ 2008; 28: 6516–25. Article  CAS  PubMed  PubMed Central  Google Scholar  * Shirayama Y, Ishida H, Iwata M, Hazama GI, Kawahara R,

Duman RS . Stress increases dynorphin immunoreactivity in limbic brain regions and dynorphin antagonism produces antidepressant-like effects. _J neurochem_ 2004; 90: 1258–68. Article  CAS 

PubMed  Google Scholar  * Winkler CW, Hermes SM, Chavkin CI, Drake CT, Morrison SF, Aicher SA . Kappa opioid receptor (KOR) and GAD67 immunoreactivity are found in OFF and NEUTRAL cells in

the rostral ventromedial medulla. _J Neurophysiol_ 2006; 96: 3465–73. Article  CAS  PubMed  Google Scholar  * Neugebauer V, Li W, Bird GC, Han JS . The amygdala and persistent pain.

_Neuroscientist_ 2004; 10: 221–34. Article  PubMed  Google Scholar  * Gutstein HB, Mansour A, Watson SJ, Akil H, Fields HL . Mu and kappa opioid receptors in periaqueductal gray and rostral

ventromedial medulla. _Neuroreport_ 1998; 9: 1777–81. Article  CAS  PubMed  Google Scholar  * Clark CR, Birchmore B, Sharif NA, Hunter JC, Hill RG, Hughes J . PD117302: a selective agonist

for the kappa-opioid receptor. _Br J Pharmacol_ 1988; 93: 618–26. Article  CAS  PubMed  PubMed Central  Google Scholar  * Lahti RA, Mickelson MM, McCall JM, Von Voigtlander PF . [3H]U-69593

a highly selective ligand for the opioid kappa receptor. _Eur J Pharmacol_ 1985; 109: 281–4. Article  CAS  PubMed  Google Scholar  * Hunter JC, Leighton GE, Meecham KG, Boyle SJ, Horwell DC,

Rees DC, _et al_. CI-977, a novel and selective agonist for the kappa-opioid receptor. _Br J Pharmacol_ 1990; 101: 183–9. Article  CAS  PubMed  PubMed Central  Google Scholar  * Lahti RA,

VonVoigtlander PF, Barsuhn C . Properties of a selective kappa agonist, U-50,488H. _Life Sci_ 1982; 31: 2257–60. Article  CAS  PubMed  Google Scholar  * Pan ZZ . mu-Opposing actions of the

kappa-opioid receptor. _Trends Pharmacol Sci_ 1998; 19: 94–8. Article  CAS  PubMed  Google Scholar  * Mansour A, Hoversten MT, Taylor LP, Watson SJ, Akil H . The cloned mu, delta and kappa

receptors and their endogenous ligands: evidence for two opioid peptide recognition cores. _Brain Res_ 1995; 700: 89–98. Article  CAS  PubMed  Google Scholar  * Land BB, Bruchas MR, Lemos

JC, Xu M, Melief EJ, Chavkin C . The dysphoric component of stress is encoded by activation of the dynorphin kappa-opioid system. _J Neurosci_ 2008; 28: 407–14. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Schwarzer C . 30 years of dynorphins--new insights on their functions in neuropsychiatric diseases. _Pharmacol Ther_ 2009; 123: 353–70. Article  CAS  PubMed 

PubMed Central  Google Scholar  * Day R, Lazure C, Basak A, Boudreault A, Limperis P, Dong W, _et al_. Prodynorphin processing by proprotein convertase 2. Cleavage at single basic residues

and enhanced processing in the presence of carboxypeptidase activity. _J Biol Chem_ 1998; 273: 829–36. Article  CAS  PubMed  Google Scholar  * Yakovleva T, Bazov I, Cebers G, Marinova Z,

Hara Y, Ahmed A, _et al_. Prodynorphin storage and processing in axon terminals and dendrites. _FASEB J_ 2006; 20: 2124–6. Article  CAS  PubMed  Google Scholar  * Shippenberg TS, Zapata A,

Chefer VI . Dynorphin and the pathophysiology of drug addiction. _Pharmacol Ther_ 2007; 116: 306–21. Article  CAS  PubMed  PubMed Central  Google Scholar  * Mysels D, Sullivan MA . The

kappa-opiate receptor impacts the pathophysiology and behavior of substance use. _Am J Addict_ 2009; 18: 272–6. Article  PubMed  PubMed Central  Google Scholar  * Chartoff EH, Potter D,

Damez-Werno D, Cohen BM, Carlezon WA Jr . Exposure to the selective kappa-opioid receptor agonist salvinorin A modulates the behavioral and molecular effects of cocaine in rats.

_Neuropsychopharmacology_ 2008; 33: 2676–87. Article  CAS  PubMed  Google Scholar  * Di Chiara G, Imperato A . Drugs abused by humans preferentially increase synaptic dopamine concentrations

in the mesolimbic system of freely moving rats. _Proc Natl Acad Sci USA_ 1988; 85: 5274–8. Article  CAS  PubMed  PubMed Central  Google Scholar  * Margolis EB, Hjelmstad GO, Bonci A, Fields

HL . Kappa-opioid agonists directly inhibit midbrain dopaminergic neurons. _J Neurosci_ 2003; 23: 9981–6. Article  CAS  PubMed  PubMed Central  Google Scholar  * Ukai M, Mizutani M,

Kameyama T . Opioid peptides selective for receptor types modulate cocaine-induced behavioral responses in mice. _Nihon Shinkei Seishin Yakurigaku Zasshi_ 1994; 14: 153–9. CAS  PubMed 

Google Scholar  * Crawford CA, McDougall SA, Bolanos CA, Hall S, Berger SP . The effects of the kappa agonist U-50,488 on cocaine-induced conditioned and unconditioned behaviors and Fos

immunoreactivity. _Psychopharmacology (Berl)_ 1995; 120: 392–9. Article  CAS  Google Scholar  * Suzuki T, Shiozaki Y, Masukawa Y, Misawa M, Nagase H . The role of mu- and kappa-opioid

receptors in cocaine-induced conditioned place preference. _Jpn J Pharmacol_ 1992; 58: 435–42. Article  CAS  PubMed  Google Scholar  * Shippenberg TS, LeFevour A, Heidbreder C . kappa-Opioid

receptor agonists prevent sensitization to the conditioned rewarding effects of cocaine. _J Pharmacol Exp Ther_ 1996; 276: 545–54. CAS  PubMed  Google Scholar  * Glick SD, Maisonneuve IM,

Raucci J, Archer S . Kappa opioid inhibition of morphine and cocaine self-administration in rats. _Brain Res_ 1995; 681: 147–52. Article  CAS  PubMed  Google Scholar  * Negus SS, Mello NK,

Portoghese PS, Lin CE . Effects of kappa opioids on cocaine self-administration by rhesus monkeys. _J Pharmacol Exp Ther_ 1997; 282: 44–55. CAS  PubMed  Google Scholar  * Mello NK, Negus SS

. Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys. _J Pharmacol Exp Ther_ 1998; 286: 812–24. CAS  PubMed  Google Scholar  * Schenk S, Partridge

B, Shippenberg TS . U69593, a kappa-opioid agonist, decreases cocaine self-administration and decreases cocaine-produced drug-seeking. _Psychopharmacology (Berl)_ 1999; 144: 339–46. Article

  CAS  Google Scholar  * Schenk S, Partridge B, Shippenberg TS . Reinstatement of extinguished drug-taking behavior in rats: effect of the kappa-opioid receptor agonist, U69593.

_Psychopharmacology (Berl)_ 2000; 151: 85–90. Article  CAS  Google Scholar  * Maisonneuve IM, Archer S, Glick SD . U50,488, a kappa opioid receptor agonist, attenuates cocaine-induced

increases in extracellular dopamine in the nucleus accumbens of rats. _Neurosci Lett_ 1994; 181: 57–60. Article  CAS  PubMed  Google Scholar  * Xu M, Petraschka M, McLaughlin JP, Westenbroek

RE, Caron MG, Lefkowitz RJ, _et al_. Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance. _J Neurosci_ 2004; 24:

4576–84. Article  CAS  PubMed  PubMed Central  Google Scholar  * Nakazawa T, Furuya Y, Kaneko T, Yamatsu K . Spinal kappa receptor-mediated analgesia of E-2078, a systemically active

dynorphin analog, in mice. _J Pharmacol Exp Ther_ 1991; 256: 76–81. CAS  PubMed  Google Scholar  * DeHaven-Hudkins DL, Dolle RE . Peripherally restricted opioid agonists as novel analgesic

agents. _Curr Pharm Des_ 2004; 10: 743–57. Article  CAS  PubMed  Google Scholar  * Pan ZZ, Tershner SA, Fields HL . Cellular mechanism for anti-analgesic action of agonists of the

kappa-opioid receptor. _Nature_ 1997; 389: 382–5. Article  CAS  PubMed  Google Scholar  * Simonin F, Valverde O, Smadja C, Slowe S, Kitchen I, Dierich A, _et al_. Disruption of the

kappa-opioid receptor gene in mice enhances sensitivity to chemical visceral pain, impairs pharmacological actions of the selective kappa-agonist U-50,488H and attenuates morphine

withdrawal. _EMBO J_ 1998; 17: 886–97. Article  CAS  PubMed  PubMed Central  Google Scholar  * Kieffer BL, Gaveriaux-Ruff C . Exploring the opioid system by gene knockout. _Prog Neurobiol_

2002; 66: 285–306. Article  CAS  PubMed  Google Scholar  * Aldrich JV, McLaughlin JP . Peptide kappa opioid receptor ligands: potential for drug development. _AAPS J_ 2009; 11: 312–22.

Article  CAS  PubMed  PubMed Central  Google Scholar  * Riviere PJ . Peripheral kappa-opioid agonists for visceral pain. _Br J Pharmacol_ 2004; 141: 1331–4. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Stein C, Clark JD, Oh U, Vasko MR, Wilcox GL, Overland AC, _et al_. Peripheral mechanisms of pain and analgesia. _Brain Res Rev_ 2009; 60: 90–113. Article  CAS 

PubMed  Google Scholar  * Stein C, Lang LJ . Peripheral mechanisms of opioid analgesia. _Curr Opin Pharmacol_ 2009; 9: 3–8. Article  CAS  PubMed  Google Scholar  * Binder W, Machelska H,

Mousa S, Schmitt T, Riviere PJ, Junien JL, _et al_. Analgesic and antiinflammatory effects of two novel kappa-opioid peptides. _Anesthesiology_ 2001; 94: 1034–44. Article  CAS  PubMed 

Google Scholar  * Jolivalt CG, Jiang Y, Freshwater JD, Bartoszyk GD, Calcutt NA . Dynorphin A, kappa opioid receptors and the antinociceptive efficacy of asimadoline in

streptozotocin-induced diabetic rats. _Diabetologia_ 2006; 49: 2775–85. Article  CAS  PubMed  Google Scholar  * Ko MC, Tuchman JE, Johnson MD, Wiesenauer K, Woods JH . Local administration

of mu or kappa opioid agonists attenuates capsaicin-induced thermal hyperalgesia via peripheral opioid receptors in rats. _Psychopharmacology (Berl)_ 2000; 148: 180–5. Article  CAS  Google

Scholar  * Barber A, Bartoszyk GD, Bender HM, Gottschlich R, Greiner HE, Harting J, _et al_. A pharmacological profile of the novel, peripherally-selective kappa-opioid receptor agonist, EMD

61753. _Br J Pharmacol_ 1994; 113: 1317–27. Article  CAS  PubMed  PubMed Central  Google Scholar  * Joshi SK, Su X, Porreca F, Gebhart GF . kappa -opioid receptor agonists modulate visceral

nociception at a novel, peripheral site of action. _J Neurosci_ 2000; 20: 5874–9. Article  CAS  PubMed  PubMed Central  Google Scholar  * Wang Y, Tang K, Inan S, Siebert D, Holzgrabe U, Lee

DY, _et al_. Comparison of pharmacological activities of three distinct kappa ligands (Salvinorin A, TRK-820 and 3FLB) on kappa opioid receptors _in vitro_ and their antipruritic and

antinociceptive activities _in vivo_. _J Pharmacol Exp Ther_ 2005; 312: 220–30. Article  CAS  PubMed  Google Scholar  * Pfeiffer A, Brantl V, Herz A, Emrich HM . Psychotomimesis mediated by

kappa opiate receptors. _Science_ 1986; 233: 774–6. Article  CAS  PubMed  Google Scholar  * Wadenberg ML . A review of the properties of spiradoline: a potent and selective kappa-opioid

receptor agonist. _CNS Drug Rev_ 2003; 9: 187–98. Article  CAS  PubMed  PubMed Central  Google Scholar  * Bals-Kubik R, Ableitner A, Herz A, Shippenberg TS . Neuroanatomical sites mediating

the motivational effects of opioids as mapped by the conditioned place preference paradigm in rats. _J Pharmacol Exp Ther_ 1993; 264: 489–95. CAS  PubMed  Google Scholar  * Mague SD, Pliakas

AM, Todtenkopf MS, Tomasiewicz HC, Zhang Y, Stevens WC Jr, _et al_. Antidepressant-like effects of kappa-opioid receptor antagonists in the forced swim test in rats. _J Pharmacol Exp Ther_

2003; 305: 323–30. Article  CAS  PubMed  Google Scholar  * Carlezon WA Jr, Beguin C, DiNieri JA, Baumann MH, Richards MR, Todtenkopf MS, _et al_. Depressive-like effects of the kappa-opioid

receptor agonist salvinorin A on behavior and neurochemistry in rats. _J Pharmacol Exp Ther_ 2006; 316: 440–7. Article  CAS  PubMed  Google Scholar  * Carlezon WA Jr, Beguin C, Knoll AT,

Cohen BM . Kappa-opioid ligands in the study and treatment of mood disorders. _Pharmacol Ther_ 2009; 123: 334–43. Article  CAS  PubMed  PubMed Central  Google Scholar  * Shippenberg TS, Herz

A . Place preference conditioning reveals the involvement of D1-dopamine receptors in the motivational properties of mu- and kappa-opioid agonists. _Brain Res_ 1987; 436: 169–72. Article 

CAS  PubMed  Google Scholar  * Zhang Y, Butelman ER, Schlussman SD, Ho A, Kreek MJ . Effects of the plant-derived hallucinogen salvinorin A on basal dopamine levels in the caudate putamen

and in a conditioned place aversion assay in mice: agonist actions at kappa opioid receptors. _Psychopharmacology (Berl)_ 2005; 179: 551–8. Article  CAS  Google Scholar  * Bruchas MR, Land

BB, Aita M, Xu M, Barot SK, Li S, _et al_. Stress-induced p38 mitogen-activated protein kinase activation mediates kappa-opioid-dependent dysphoria. _J Neurosci_ 2007; 27: 11614–23. Article

  CAS  PubMed  PubMed Central  Google Scholar  * Sante AB, Nobre MJ, Brandao ML . Place aversion induced by blockade of mu or activation of kappa opioid receptors in the dorsal

periaqueductal gray matter. _Behav Pharmacol_ 2000; 11: 583–9. Article  CAS  PubMed  Google Scholar  * Redila VA, Chavkin C . Stress-induced reinstatement of cocaine seeking is mediated by

the kappa opioid system. _Psychopharmacology (Berl)_ 2008; 200: 59–70. Article  CAS  Google Scholar  * Valdez GR, Platt DM, Rowlett JK, Ruedi-Bettschen D, Spealman RD . Kappa agonist-induced

reinstatement of cocaine seeking in squirrel monkeys: a role for opioid and stress-related mechanisms. _J Pharmacol Exp Ther_ 2007; 323: 525–33. Article  CAS  PubMed  Google Scholar  *

Carey AN, Borozny K, Aldrich JV, McLaughlin JP . Reinstatement of cocaine place-conditioning prevented by the peptide kappa-opioid receptor antagonist arodyn. _Eur J Pharmacol_ 2007; 569:

84–9. Article  CAS  PubMed  PubMed Central  Google Scholar  * Beardsley PM, Howard JL, Shelton KL, Carroll FI . Differential effects of the novel kappa opioid receptor antagonist, JDTic, on

reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats. _Psychopharmacology (Berl)_ 2005; 183: 118–26. Article  CAS 

Google Scholar  * Neumeyer JL, Bidlack JM, Zong R, Bakthavachalam V, Gao P, Cohen DJ, _et al_. Synthesis and opioid receptor affinity of morphinan and benzomorphan derivatives: mixed kappa

agonists and mu agonists/antagonists as potential pharmacotherapeutics for cocaine dependence. _J Med Chem_ 2000; 43: 114–22. Article  CAS  PubMed  Google Scholar  * Wang YJ, Tao YM, Li FY,

Wang YH, Xu XJ, Chen J, _et al_. Pharmacological characterization of ATPM [(−)-3-aminothiazolo[5,4-b]-N-cyclopropylmethylmorphinan hydrochloride], a novel mixed kappa-agonist and

mu-agonist/-antagonist that attenuates morphine antinociceptive tolerance and heroin self-administration behavior. _J Pharmacol Exp Ther_ 2009; 329: 306–13. Article  CAS  PubMed  PubMed

Central  Google Scholar  * Gear RW, Miaskowski C, Gordon NC, Paul SM, Heller PH, Levine JD . The kappa opioid nalbuphine produces gender- and dose-dependent analgesia and antianalgesia in

patients with postoperative pain. _Pain_ 1999; 83: 339–45. Article  CAS  PubMed  Google Scholar  * Takemori AE, Loh HH, Lee NM . Suppression by dynorphin A and [des-Tyr1]dynorphin A peptides

of the expression of opiate withdrawal and tolerance in morphine-dependent mice. _J Pharmacol Exp Ther_ 1993; 266: 121–4. CAS  PubMed  Google Scholar  * Vanderah TW, Gardell LR, Burgess SE,

Ibrahim M, Dogrul A, Zhong CM, _et al_. Dynorphin promotes abnormal pain and spinal opioid antinociceptive tolerance. _J Neurosci_ 2000; 20: 7074–9. Article  CAS  PubMed  PubMed Central 

Google Scholar  * Koob GF, Volkow ND . Neurocircuitry of addiction. _Neuropsychopharmacology_; 35: 217–38. * Tao YM, Li QL, Zhang CF, Xu XJ, Chen J, Ju YW, _et al_. LPK-26, a novel

kappa-opioid receptor agonist with potent antinociceptive effects and low dependence potential. _Eur J Pharmacol_ 2008; 584: 306–11. Article  CAS  PubMed  Google Scholar  * Specker S,

Wananukul W, Hatsukami D, Nolin K, Hooke L, Kreek MJ, _et al_. Effects of dynorphin A(1–13) on opiate withdrawal in humans. _Psychopharmacology (Berl)_ 1998; 137: 326–32. Article  CAS 

Google Scholar  * Greenwald MK, Stitzer ML, Haberny KA . Human pharmacology of the opioid neuropeptide dynorphin A(1–13). _J Pharmacol Exp Ther_ 1997; 281: 1154–63. CAS  PubMed  Google

Scholar  * Trigo JM, Martin-Garcia E, Berrendero F, Robledo P, Maldonado R . The endogenous opioid system: A common substrate in drug addiction. _Drug Alcohol Depend_ 2009; 108: 183–94.

Article  CAS  PubMed  Google Scholar  * Tomasiewicz HC, Todtenkopf MS, Chartoff EH, Cohen BM, Carlezon WA Jr . The kappa-opioid agonist U69,593 blocks cocaine-induced enhancement of brain

stimulation reward. _Biol Psychiatry_ 2008; 64: 982–8. Article  CAS  PubMed  PubMed Central  Google Scholar  * Walsh SL, Geter-Douglas B, Strain EC, Bigelow GE . Enadoline and butorphanol:

evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans. _J Pharmacol Exp Ther_ 2001; 299: 147–58. CAS  PubMed  Google Scholar  * Heidbreder CA,

Goldberg SR, Shippenberg TS . The kappa-opioid receptor agonist U-69593 attenuates cocaine-induced behavioral sensitization in the rat. _Brain Res_ 1993; 616: 335–8. Article  CAS  PubMed 

Google Scholar  * Chefer VI, Moron JA, Hope B, Rea W, Shippenberg TS . Kappa-opioid receptor activation prevents alterations in mesocortical dopamine neurotransmission that occur during

abstinence from cocaine. _Neuroscience_ 2000; 101: 619–27. Article  CAS  PubMed  Google Scholar  * Gehrke BJ, Chefer VI, Shippenberg TS . Effects of acute and repeated administration of

salvinorin A on dopamine function in the rat dorsal striatum. _Psychopharmacology (Berl)_ 2008; 197: 509–17. Article  CAS  Google Scholar  * McLaughlin JP, Land BB, Li S, Pintar JE, Chavkin

C . Prior activation of kappa opioid receptors by U50,488 mimics repeated forced swim stress to potentiate cocaine place preference conditioning. _Neuropsychopharmacology_ 2006; 31: 787–94.

Article  CAS  PubMed  Google Scholar  * McLaughlin JP, Marton-Popovici M, Chavkin C . Kappa opioid receptor antagonism and prodynorphin gene disruption block stress-induced behavioral

responses. _J Neurosci_ 2003; 23: 5674–83. Article  CAS  PubMed  PubMed Central  Google Scholar  * Mello NK, Negus SS . Interactions between kappa opioid agonists and cocaine. Preclinical

studies. _Ann N Y Acad Sci_ 2000; 909: 104–32. Article  CAS  PubMed  Google Scholar  * Archer S, Glick SD, Bidlack JM . Cyclazocine revisited. _Neurochem Res_ 1996; 21: 1369–73. Article  CAS

  PubMed  Google Scholar  * Bowen CA, Negus SS, Zong R, Neumeyer JL, Bidlack JM, Mello NK . Effects of mixed-action kappa/mu opioids on cocaine self-administration and cocaine discrimination

by rhesus monkeys. _Neuropsychopharmacology_ 2003; 28: 1125–39. Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by the National Basic

Research Program grant from the Ministry of Science and Technology of China (No 2009CB522000, 2009ZX09301-001), National Natural Science Fundation of China (30873050) and a fund granted by

the Chinese Academy of Sciences (KSCX2-YW-R-253). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, 210046, China Yu-hua Wang

* State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China Yu-hua Wang, Jian-feng Sun, Yi-min Tao, Zhi-qiang Chi 

& Jing-gen Liu Authors * Yu-hua Wang View author publications You can also search for this author inPubMed Google Scholar * Jian-feng Sun View author publications You can also search for

this author inPubMed Google Scholar * Yi-min Tao View author publications You can also search for this author inPubMed Google Scholar * Zhi-qiang Chi View author publications You can also

search for this author inPubMed Google Scholar * Jing-gen Liu View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to

Jing-gen Liu. RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Wang, Yh., Sun, Jf., Tao, Ym. _et al._ The role of κ-opioid receptor activation in

mediating antinociception and addiction. _Acta Pharmacol Sin_ 31, 1065–1070 (2010). https://doi.org/10.1038/aps.2010.138 Download citation * Received: 31 May 2010 * Accepted: 20 July 2010 *

Published: 23 August 2010 * Issue Date: September 2010 * DOI: https://doi.org/10.1038/aps.2010.138 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this

content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative

KEYWORDS * κ-opioid receptor * dynorphin * desensitization * antinociception * tolerance * addiction * drug withdrawal * cocaine reward * negative mood state