RPEP-00094 · 1988Leu-enkephalin and leu-enkephalinamide inhibited electrical self-stimulation in the substantia nigra/ventral tegmental area (SN-VTA) but not the medial forebrain bundle/lateral hypothalamus (MFB-LH). However, injection into MFB-LH facilitated self-stimulation of the distant SN-VTA.
Ala-leu-enkephalin injected into SN-VTA actually facilitated its self-stimulation (opposite to leu-enkephalin). The same peptide in MFB-LH facilitated SN-VTA stimulation like the other enkephalins.
Dynorphin A(1-13) injected into SN-VTA facilitated its self-stimulation. Injection into MFB-LH had no effect.
Met-enkephalin had no direct or indirect effects in either region.
These differences likely reflect different receptor preferences in the SN-VTA neural organization.
Singh, J; Desiraju, T · Animal Study
RPEP-00213 · 1991Opiate tolerance involves multiple mechanisms: environmental learning, NMDA receptor involvement, second messenger system adaptations, and altered intracellular signaling. Receptor numbers change minimally.
Trujillo, K A; Akil, H · Review
RPEP-00240 · 1992Dynorphin(1-13) ICV produced dose-dependent antinociception. It prevented acute morphine tolerance development. Potency order: beta-endorphin > morphine > dynorphin >> met-enkephalin.
Kishioka, S; Morita, N; Kitabata, Y; Yamanishi, T; Miyamoto, Y; Ozaki, M; Yamamoto, H · Animal Study
RPEP-00244 · 1992Chimeric peptides coupling opioid peptides to BBB transport vectors allow brain delivery of enkephalin and dynorphin analogs in vivo. The strategy has advantages for addiction drug development.
Pardridge, W M · Review
RPEP-00270 · 1993Morphine produced distinct changes in multiple CSF opioid peptide species, with patterns differing from plasma changes. HPLC confirmed specific peptide identification.
Natsuki, R; Dewey, W L · Animal Study
RPEP-00272 · 1993Thymosin alpha 1 fully restored cocaine-suppressed antibody responses. Thymopentin partially restored them. Effect confirmed at the individual splenocyte level.
Ravagnan, G; Falchetti, R; Lanzilli, G; Di Francesco, P; Gaziano, R; Favalli, C; Garaci, E · Animal Study
RPEP-00273 · 1993Chronic ICV NPFF (5 micrograms/h for 10 days) downregulated mu opioid binding sites. Dynorphin and enkephalin mRNA were unchanged.
Rothman, R B; Brady, L S; Xu, H; Long, J B · Animal Study
RPEP-00337 · 1995Chronic morphine increased dynorphin A and B in the nucleus accumbens and met-enkephalin in the striatum, with distinct withdrawal-phase patterns across brain regions.
Nylander, I; Vlaskovska, M; Terenius, L · Animal Study
RPEP-00373 · 1996Orphanin FQ/nociceptin suppressed dopamine release in the nucleus accumbens, acting opposite to classical opioids which typically increase dopamine in this reward-related region.
Murphy, N P; Ly, H T; Maidment, N T · Animal Study
RPEP-00410 · 1997Mu and delta opioid receptors mediate alcohol's rewarding properties while kappa receptors oppose them, with all three endogenous opioid peptide families playing distinct roles in addiction.
Herz, A · Review
RPEP-00596 · 2000Chronic nandrolone treatment altered met-enkephalin and dynorphin concentrations in limbic and striatal brain regions, providing a neurochemical mechanism for steroid-associated mood and behavioral disturbances.
Johansson, P; Hallberg, M; Kindlundh, A; Nyberg, F · Animal Study
RPEP-00601 · 2000Repeated ethanol produced both short-term (24h) and persistent (2-week) alterations in enkephalin and dynorphin tissue concentrations in mesolimbic reward regions, providing a neurochemical basis for alcohol craving and relapse.
Lindholm, S; Ploj, K; Franck, J; Nylander, I · Animal Study
RPEP-00613 · 2000Alcohol-preferring mice had lower baseline nociceptin and dynorphin B in reward regions, with alcohol consumption producing additional changes in met-enkephalin levels, linking opioid/nociceptin system configuration to alcohol preference.
Ploj, K; Roman, E; Gustavsson, L; Nylander, I · Animal Study
RPEP-00739 · 2002Opioid gene knockouts reveal distinct, non-redundant roles: enkephalins in analgesia and reward, beta-endorphin in stress analgesia and respiratory control, dynorphins in pain and emotional regulation — each family has a specific functional niche.
Kieffer, Brigitte L; Gavériaux-Ruff, Claire · Review
RPEP-00771 · 2002BPC-157 attenuated chronic amphetamine-induced tolerance, behavioral sensitization, and withdrawal disturbances in rats, demonstrating comprehensive dopamine system stabilization against stimulant drug-induced neuroplasticity.
Sikiric, Predrag; Jelovac, Nikola; Jelovac-Gjeldum, Andjelka; Dodig, Goran; Staresinic, Mario; Anic, Tomislav; Zoricic, Ivan; Rak, Davor; Perovic, Darko; Aralica, Gorana; Buljat, Gojko; Prkacin, Ingrid; Lovric-Bencic, Martina; Separovic, Jadranka; Seiwerth, Sven; Rucman, Rudolf; Petek, Marijan; Turkovic, Branko; Ziger, Tihomil; Boban-Blagaic, Alenka; Bedekovic, Vlado; Tonkic, Ante; Babic, Slaven · Animal Study
RPEP-00886 · 2004BPC-157 protected against acute ethanol toxicity (reduced mortality, behavioral impairment, gastric damage) and chronic alcohol effects (reduced intake, liver protection), demonstrating comprehensive anti-alcohol therapeutic potential.
Blagaic, Alenka Boban; Blagaic, Vladimir; Romic, Zeljko; Sikiric, Predrag · Animal Study
RPEP-00946 · 2004Maternal separation significantly altered maternal care patterns but produced only subtle changes in adult offspring brain opioid peptides and behavior, suggesting compensatory mechanisms partially buffer against early-life adversity effects.
Marmendal, Maarit; Roman, Erika; Eriksson, C J Peter; Nylander, Ingrid; Fahlke, Claudia · Animal Study
RPEP-00971 · 2004Amygdalar NPY-CRF interactions constitute an anxiety-resilience balance: CRF promotes fear/anxiety through CRF1 while NPY opposes through Y1 receptors — imbalance drives anxiety disorders, PTSD, and addiction.
Sajdyk, Tammy J; Shekhar, Anantha; Gehlert, Donald R · Review
RPEP-01017 · 2005CRF/urocortin system activation drives the stress/withdrawal component of cannabis, nicotine, and alcohol dependence through CRF1-mediated anxiety during abstinence, creating a negative reinforcement cycle that maintains substance use.
Bruijnzeel, Adrie W; Gold, Mark S · Review
RPEP-01087 · 2005Adolescent nicotine exposure produced lasting increases in CRF-like and NPY-like immunoreactivity in amygdala and hypothalamic stress regions in adult rats, correlating with increased anxiety — adolescent nicotine permanently alters brain stress peptide systems.
Slawecki, Craig J; Thorsell, Annika K; El Khoury, Aram; Mathé, Aleksander A; Ehlers, Cindy L · Animal Study
RPEP-01112 · 2006Ghrelin directly excited ventral tegmental area (VTA) dopamine neurons and increased excitatory synaptic inputs while promoting food-seeking behavior — establishing the molecular neurocircuit linking the hunger hormone to the brain's reward/motivation system.
Abizaid, Alfonso; Liu, Zhong-Wu; Andrews, Zane B; Shanabrough, Marya; Borok, Erzsebet; Elsworth, John D; Roth, Robert H; Sleeman, Mark W; Picciotto, Marina R; Tschöp, Matthias H; Gao, Xiao-Bing; Horvath, Tamas L · Animal Study
RPEP-01118 · 2006BPC-157's protective effects against acute ethanol toxicity and chronic alcohol consumption were modulated by NO synthase inhibitor L-NAME, implicating the nitric oxide system as a mediating pathway in BPC-157's anti-alcohol therapeutic mechanism.
Boban-Blagaic, Alenka; Blagaic, Vladimir; Romic, Zeljko; Jelovac, Nikola; Dodig, Goran; Rucman, Rudolf; Petek, Marijan; Turkovic, Branko; Seiwerth, Sven; Sikiric, Predrag · Animal Study
RPEP-01145 · 2006Kappa-opioid (dynorphin) and mu-opioid (endorphin/enkephalin) systems differentially regulated sucrose preference versus food-reinforced operant behavior in mice — different opioid families mediate different components of food reward and palatable eating.
Hayward, Michael D; Schaich-Borg, Alexandra; Pintar, John E; Low, Malcolm J · Animal Study
RPEP-01237 · 2007Ethanol-induced changes in brain opioid peptides (dynorphin, enkephalin) in adult Wistar rats were modulated by early postnatal environment (maternal separation), demonstrating gene × early environment interaction programming adult opioid system alcohol sensitivity.
Gustafsson, L; Zhou, Q; Nylander, I · Animal Study
RPEP-01372 · 2008In-vivo microdialysis showed acute ethanol directly triggered beta-endorphin and met-enkephalin release in the central amygdala, providing real-time evidence for alcohol's emotional/anxiolytic effects through local opioid peptide release in the brain's fear center.
Lam, Minh P; Marinelli, Peter W; Bai, Li; Gianoulakis, Christina · Animal Study
RPEP-01373 · 2008Pro-ghrelin and GHS-R1A gene polymorphisms and haplotypes were associated with heavy alcohol use and BMI in humans, providing genetic evidence linking the ghrelin system to both alcohol addiction vulnerability and body weight regulation.
Landgren, Sara; Jerlhag, Elisabet; Zetterberg, Henrik; Gonzalez-Quintela, Arturo; Campos, Joaquin; Olofsson, Ulrica; Nilsson, Staffan; Blennow, Kaj; Engel, Jörgen A · Cross Sectional
RPEP-01449 · 2009Peripheral ghrelin activates mesolimbic dopamine reward pathways (VTA → nucleus accumbens), linking the hunger hormone to food reward and hedonic eating — a gut-brain-dopamine axis connecting appetite to pleasure and potentially to addictive eating behavior.
Abizaid, Alfonso · Review
RPEP-01949 · 2012Neuropeptide Y (NPY) in the central amygdala (CeA) plays a critical role in the transition to alcohol dependence. Mice lacking the NPY gene show both high anxiety and high alcohol drinking. Rats bred to prefer alcohol have baseline NPY deficits in the CeA, and infusing NPY into the CeA suppresses excessive drinking in both alcohol-preferring and alcohol-dependent rats. The author proposes that NPY modulates anxiety via Y2 receptor regulation of NPY release, while it reduces alcohol drinking via Y2 receptor regulation of GABA release — two distinct mechanisms through the same receptor.
Gilpin, Nicholas W · Review
RPEP-05285 · 2021Nicotine withdrawal (24-48h) dramatically increased NPY and receptor (Y1, Y2, Y5) mRNA levels across the mesocorticolimbic system, suggesting NPY signaling upregulation as a compensatory response to withdrawal-induced negative affect.
Birdogan, Ali; Salur, Elif; Tuzcu, Fulya; Gokmen, Ramazan C; Ozturk Bintepe, Meliha; Aypar, Buket; Keser, Aysegul; Balkan, Burcu; Koylu, Ersin O; Kanit, Lutfiye; Gozen, Oguz · Animal
RPEP-05340 · 2021Resilient female rats had higher Y2R mRNA expression in the central amygdala and higher NPY protein levels in the BNST compared to vulnerable and control rats after traumatic stress exposure.
Denny, Ray R; Connelly, Krista L; Ghilotti, Marco G; Meissler, Joseph J; Yu, Daohai; Eisenstein, Toby K; Unterwald, Ellen M · Animal
RPEP-05424 · 2021Acute GLP-1 injection consistently stimulates the physiological stress response in rodents (increased stress hormones). Long-term GLP-1 exposure shows anxiolytic and antidepressant-like effects in animal models. In clinical studies, prolonged GLP-1 analogue treatment in type 2 diabetes patients improved mood and general psychological wellbeing. However, these clinical benefits may be confounded by associated weight loss and improved glycemic control. GLP-1 acts on brain areas involved in stress response and emotion regulation, supporting a potential direct role beyond appetite suppression.
Guerrero-Hreins, Eva; Goldstone, Anthony P; Brown, Robyn M; Sumithran, Priya · Review
RPEP-05506 · 2021Multiple neuropeptide systems (CRF, dynorphin, substance P, nociceptin, orexin, vasopressin, NPY, endocannabinoids, and others) are dysregulated in the extended amygdala/habenula during drug withdrawal, driving hyperkatifeia that motivates compulsive drug seeking across substances.
Koob, George F · Review
RPEP-09081 · 2024Among people with type 2 diabetes, semaglutide was linked to a lower risk of medical encounters related to tobacco use disorder compared to other diabetes drug classes. The effect was strongest when comparing semaglutide to insulin. It was weakest compared to other GLP-1 receptor agonists, suggesting the effect may be partly a GLP-1 class effect rather than unique to semaglutide.
Semaglutide users also had fewer prescriptions for smoking cessation medications and less counseling for smoking. These patterns held regardless of whether patients were also obese.
Popovic, Djordje S; Patoulias, Dimitrios; Koufakis, Theocharis; Karakasis, Paschalis; Ruža, Ieva; Papanas, Nikolaos · Review/Commentary
RPEP-09122 · 2024Oxytocin shows dose-dependent effects on alcohol use behavior: low doses do not significantly affect drinking or tolerance, but higher doses given before alcohol exposure produce varying behavioral and physiological results. In preclinical (animal) studies, oxytocin reduced withdrawal symptoms and alcohol self-administration. In clinical (human) studies, oxytocin may decrease neural cue reactivity (how strongly the brain responds to alcohol-related cues) and withdrawal symptoms.
The timing and dose of oxytocin appear critical — the peptide seems to work by strengthening stress-coping mechanisms and reducing anxiety, which are key drivers of alcohol craving and relapse. However, results are inconsistent across studies, and the optimal dosing and treatment protocols remain unclear.
Rastogi, Kriti; Weerts, Elise M; Ellis, Jennifer D · Review
RPEP-09337 · 2024Exenatide RCT: no significant reduction in heavy drinking days vs placebo overall (95% CI -7.4 to 19.4, p=0.37), but fMRI showed reduced brain reward center cue reactivity in obese subgroup. Dulaglutide secondary analysis: 29% more likely to reduce alcohol intake (relative effect 0.71, CI 0.52-0.97, p=0.04). Observational studies showed fewer alcohol-related healthcare events with GLP-1 RAs.
Subhani, Mohsan; Dhanda, Ashwin; King, James A; Warren, Fiona C; Creanor, Siobhan; Davies, Melanie J; Eldeghaidy, Sally; Bawden, Stephen; Gowland, Penny A; Bataller, Ramon; Greenwood, Justin; Kaar, Stephen; Bhala, Neeraj; Aithal, Guruprasad P · Review
RPEP-09966 · 2025Semaglutide suppressed cocaine taking, seeking behavior, and cocaine-evoked dopamine release, providing strong preclinical evidence for GLP-1 drugs in cocaine addiction treatment.
Aranäs, Cajsa; Caffrey, Antonia; Edvardsson, Christian E; Schmidt, Heath D; Jerlhag, Elisabet · Animal Study
RPEP-09967 · 2025Combined pharmacotherapy including GLP-1 drugs produced synergistic-like decreases in alcohol intake, supporting multi-target approaches to alcohol use disorder.
Aranäs, Cajsa; Caffrey, Antonia; Edvardsson, Christian E; Vestlund, Jesper; Schmidt, Heath D; Jerlhag, Elisabet · Animal Study