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. Author manuscript; available in PMC: 2024 Jun 15.
Published in final edited form as: Neuropharmacology. 2023 Mar 20;231:109510. doi: 10.1016/j.neuropharm.2023.109510

Table 1.

Behavioral effects of MOR, KOR, and DOR drugs in preclinical studies

Receptor Drug Type Compound Route of Administration Subregion Species Sex Pain Model Behavioral Effect Behavioral Test References
Systemic
MOR Agonist Morphine i.p. - Mouse Male Formalin Antinociceptive Licking and biting time Zeng 2021
i.p. Mouse Male CCI Increased preference behavior CPP Kai 2018
Oral Rat Both Naïve Antinociceptive (in male offspring) Hot plate test, acetic acid writhing test Ashabi 2018
Formalin Licking time
s.c. Mouse Male Hindpaw incision Increased preference behavior CPP Nwaneshiudu 2020
i.v. Rat Male SNL Antinociceptive von Frey test Navratilova 2015b
Increased preference behavior CPP
i.p. Rat Male SNL Antinociceptive von Frey test LaGraize 2006
Decreased avoidance behavior LDB
i.p. Rat Male NMDA-induced CeA lesion No effect Formalin test Manning 1995a
NMDA-induced BLA lesion Antinociceptive
i.p. Rat Male NMDA-induced CeA lesion No effect Tail flick test Manning 1995b
Fentanyl (long-term) s.c. Rat Male Naïve Pronociceptive von Frey test, Hargreaves test Wang 2022
Remifentanil (long-term) i.v. Mouse Female Naïve Increased cognitive deficits ED shift task Anderson 2021
Male No effect
Female Naïve Increased depressive-like behavior FST
Male No effect
Agonist + antagonist Morphine + naloxone s.c. + intra-NAc microinjection Rat Male Naïve Pronociceptive Hot plate test Dill 1977
s.c. + intra-CN microinjection No effect
s.c. + intra-GP microinjection No effect
Agonist + acetaldehyde dehydrogenase inhibitor Morphine + disulfram Oral Rat Male Naïve Antinociceptive Randall-Selitto test, tail flick test de Corde-Skurska 2021
Antagonist + agonist Naloxone + morphine i.p. + intra-ACC microinjection Rat Male SNL No effect von Frey test LaGraize 2006
No effect LDB
KOR Agonist U69,593 (long-term) s.c. Rat Male Naïve Increased aversion behavior CPA Tejeda 2013
U69,593 s.c. Mouse Male KOR KO on dopaminergic neurons Decreased aversive behavior CPA Chefer 2013
Antagonist nor-BNI s.c. Rat Male Naïve No effect OFT Tejeda 2015
DOR Antagonist NTI s.c. Mouse Male Naïve Increased anxiety-like behavior LDB, EPM Narita 2006b
mPFC
MOR Agonist Morphine Microinjection ACC Rat Male Incision model Increased preference behavior CPP Navratilova 2015b
No effect von Frey test
SNL Increased preference behavior CPP
No effect von Frey test
Microinjection ACC Rat Male SNL No effect von Frey test LaGraize 2006
Decreased avoidance behavior LDB
Microinjection rostral ACC, caudal ACC Rat Male SNL No effect Tail flick assay, von Frey test, Randall-Selitto test, Hargreaves test Gomtsian 2018
rostral ACC Increased preference behavior CPP
caudal ACC No effect
Microinjection ACC Rat Male CCI Antinociceptive Randall-Selitto test, hot plate test Wang 2020
Agonist + antagonist Morphine + naloxone No effect
Morphine + β-FNA No effect
Antagonist Naloxonazine Microinjection PL Rat Male Orofacial formalin Pronociceptive Face rubbing Tamaddonfard 2020
Naloxone Microinfusion PL Rat Male SNL Pronociceptive von Frey test Zeng 2018
Microinjection ACC Rat Male Incision model Decreased preference behavior CPP Navratilova 2015b
No effect von Frey test
SNL Decreased preference behavior CPP
No effect von Frey test
Antagonist + agonist β-FNA + morphine Microinjection + i.v. Antinociceptive von Frey test
Decreased preference behavior CPP
Selective ablation of MOR-expressing neurons Derm-SAP Microinjection Decreased preference behavior CPP
No effect Hargreaves test
Antagonist + agonist β-FNA + morphine Microinjection right ACC + right CeA Rat Male SNL Decreased preference behavior CPP Navratilova 2020
KOR Antagonist nor-BNI Microinfusion PL Rat Male U69,593-conditioned Decreased aversion behavior CPA Tejeda 2013
Microinfusion PL Rat Male Naïve Decreased anxiety-like behavior OFT Tejeda 2015
DOR Agonist DADLE Microinjection rostral ACC Rat Male CFA Decreased aversion behavior CPA Ma 2022
No effect Hot plate test
KNT-127 Microinfusion PL Mouse Male Naïve No effect OFT Saitoh 2018
Agonist + sodium channel activator KNT-127 + veratrine Decreased anxiety-like behavior
Antagonist Naltrindole Microinjection ACC Mouse Male Naïve Increased anxiety-like behavior LDB, EPM Narita 2006b
Amygdala
MOR Agonist Morphine Microinjection right CeA Rat Male SNL No effect von Frey test, Randall-Selitto test Navratilova 2020
Increased preference behavior CPP
left CeA No effect von Frey test, Randall-Selitto test, CPP
Microinjection BLA Rat Male Naïve Antinociceptive Tail flick test Helmstetter 1995
Microinjection BLA Rat Male Naïve Antinociceptive Tail flick test, jump test Pavlovic 1996
CeA
Microinfusion BLA Rat Male Naïve Antinociceptive Tail flick test McGaraughty 2002
DAMGO Microinjection BLA Rat Male Naïve Antinociceptive Tail flick test Helmstetter 1998
Microinjection CeA Rat Male CFA Decreased aversion behavior CPA Zhang 2013
No effect Hargreaves test
β-endorphin Microinjection BLA Rat Male Naïve Antinociceptive Tail flick test, jump test Pavlovic 1996
CeA
Agonist + antagonist Morphine + naltrexone Microinjection BLA + PAG No effect
β-endorphin + naltrexone
Antagonist CTAP Microinjection CeA Mouse Both Plantar incision model Pronociceptive von Frey test Cooper 2022
Chemogenetic inhibition of MOR-expressing PB input neurons AAVDJ-EF1a-DIO-hM4D(Gi)-mCherry Microinjection CeA Mouse Both Formalin Antinociceptive Hot plate test Liu 2022
Decreased anxiety-like behavior EPM
KOR Agonist U69,593 Microinfusion right CeA Rat Male Naïve Increased emotional-affective responses Vocalizations to noxious stimulus Hein 2021
Increased anxiety-like behavior OFT
Decreased preference behavior CPP
No effect Paw pressure test
Antagonist nor-BNI Microinfusion right CeA Rat Male SNL Decreased gabapentin-induced preference behavior CPP Navratilova 2019
No effect von Frey test
Microinfusion right CeA Rat Male Functional pain model Decreased emotional-affective responses Vocalizations to noxious stimulus Yakhnitsa 2022
Decreased anxiety-like behavior EPM
Antinociceptive von Frey test
No effects Paw pressure test
Microinfusion right CeA Rat Male Medication overuse model Antinociceptive von Frey test Xie 2017
left CeA No effect
Microinfusion right CeA Rat Male Infraorbital CCI Antinociceptive von Frey test Turnes 2022
No effect EPM
left CeA No effect von Frey test, EPM
Microinjection right CeA Rat Male SNL + capsaicin Antinociceptive Randall-Selitto test Phelps 2019
left CeA No effect
Microinjection right CeA Rat Male Functional pain model Antinociceptive Randall-Selitto test Nation 2018
left CeA No effect
DOR Agonist DPDPE Microinfusion CeA Mouse Male Naïve Pronociceptive von Frey test Zhou 2021
No effect OFT, EPM
CFA No effect von Frey test, OFT, EPM
Deltorphin II Naïve No effect von Frey test, OFT, EPM
CFA No effect Von Frey test
Decreased anxiety-like behavior OFT, EPM
DOR1 antagonist BNTX No effect
DOR2 antagonist Naltriben Increased anxiety-like behavior
Antagonist Naltrindole Microinjection BLA Mouse Male CFA Increased anxiety-like behavior LDB, EPM Narita 2006a
CCI
NAc
MOR Agonist Morphine Microinjection n.s. Rat Male Naïve Antinociceptive Hot plate test Dill 1977
Microinfusion n.s. Rat Male SNL Antinociceptive Hot plate test, Randall-Selitto test Bian 2015
DAMGO Microinjection n.s. Rat Male Naïve No effect Jaw-opening reflex Schmidt 2002
Antagonist CTOP Microinjection n.s. Rat Male DAMGO-induced antinociception Pronociceptive Jaw-opening reflex Gear 2011
Microinjection n.s. Rat Male Capsaicin-induced antinociception Pronociceptive Jaw-opening reflex Schmidt 2022
Microinjection n.s. Rat Male UFP-512-induced anxiolytic and antidepressant effects Increased anxiety- and depressive-like behavior EPM, novelty-induced hypophagia test Kabli 2014
Naloxone Microinjection n.s. Rat Male Capsaicin-induced antinociception Pronociceptive Jaw-opening reflex Gear 1999
Dopamine receptor antagonist + agonist α-flupenthixol + morphine Microinjection NAc + rostral ACC Rat Male SNL Decreased preference behavior CPP Navratilova 2015b
MOR + DOR Agonist + agonist DAMGO + DPDPE Microinjection n.s. Rat Male Naïve Antinociceptive Jaw-opening reflex Schmidt 2002
UFP-512 Microinjection n.s. Rat Male Naïve Decreased anxiety- and depressive-like behavior EPM, novelty-induced hypophagia test Kabli 2014
KOR Photoactivation of dynorphin neurons - Optical activation ventral NAc shell Mouse Both Naïve Decreased motivation Sucrose self-administration Massaly 2019
Increased aversion behavior Real-time place aversion
NAc shell cold spot Rat Male CFA Increased aversion behavior
Photostimulation ventral NAc shell Mouse Male Naïve Increased aversion behavior Real-time place aversion Al-Hasani 2015
No effect OFT
dorsal NAc shell Increased preference behavior Real-time place preference
No effect OFT
Photoactivation of dynorphin neurons + antagonist nor-BNI Microinjection NAc shell cold spot Rat Male CFA Decreased aversion behavior Real-time place aversion Massaly 2019
Agonist U69,593 Microinjection n.s. Rat Male Capsaicin-induced antinociception Pronociceptive Jaw-opening reflex Schmidt 2022
DAMGO-induced antinociception
DPDPE-induced antinociception
E-2078 Microinjection n.s. Rat Male Naïve Increased aversion behavior CPA Bals-Kubik 1993
U50,488
Microinjection n.s. Mouse Male Naïve Increased anxiety-like behavior EPM, LDB Wang 2016
Antagonist nor-BNI U50,488-induced anxiety-like behavior Decreased anxiety-like behavior EPM
Microinfusion NAc shell Rat Male Learned helplessness model Decreased depressive-like behavior Conditioned avoidance test Shirayama 2004
Microinjection ventral NAc shell Mouse Both Dynorphin neuron stimulation Decreased aversive behavior Real-time place aversion Massaly 2019
Chemogenetic silencing of dynorphin neurons Dyn2.0-hM4Di-IRES-mCherry Microinjection NAc shell cold spot Rat Male Naïve Increased motivation Sucrose self-administration
DOR Agonist DPDPE Microinjection n.s. Rat Male Naïve No effect Jaw-opening reflex Schmidt 2002
Antagonist Naltrindole Microinjection n.s. Rat Male DAMGO-induced antinociception Pronociceptive Jaw-opening reflex Gear 2011
Microinjection n.s. Rat Male Capsaicin-induced antinociception Pronociceptive Jaw-opening reflex Schmidt 2002
Microinjection n.s. Rat Male UFP-512-induced anxiolytic and antidepressant effects Increased anxiety- and depressive-like behavior EPM, novelty-induced hypophagia test Kabli 2014

β-FNA, β-funaltrexamine; BNTX, 7-benzylidenenaltrexone; CCI, chronic constriction injury; CeA, central nucleus of the amygdala; CFA, complete Freund’s adjuvant; CMS, chronic mild stress; CN, caudate nucleus; CPA, conditioned place aversion; CPP, conditioned place preference; CTOP, [Cys2-Tyr3-Orn5-Pen7]-amide; DADLE, [D-Ala2, D-Leu5]-enkephalin; DAMGO, D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin; Derm-SAP, dermorphin-saporin; DPDPE, D-Pen2,5 enkephalin D-Pen2,5-enkephalin; ED, extradimensional shift task; EPM, elevated plus maze; FST, forced swim test; GP, globus pallidus; i.p., intraperitoneal; i.v., intravenous; KO, knock out; LDB, light/dark box; mPFC, medial prefrontal cortex; NMDA, N-methyl-D-aspartate; nor-BNI, nor-binaltorphimine; n.s., not specified; NTI, naltrindole; OFT, open field test; PB, parabrachial nucleus; PL, prelimbic; RVM, rostral ventromedial medulla; s.c., subcutaneous; SNL, spinal nerve ligation; TST, tail suspension test; UFP-512, (H-Dmt-Tic-NH-CH(CH2-COOH)-Bid); vlPAG, ventrolateral periaqueductal gray