scholarly journals Resistance of Food-Maintained Operant Responding to Mechanical Punishment in Rats: Further Evidence for Weak “Affective/Motivational Pain” in Rat Models of Inflammatory and Neuropathic Pain

2021 ◽  
Vol 11 ◽  
Author(s):  
S. Stevens Negus ◽  
S. A. Marsh ◽  
E. A. Townsend
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Opioid Receptor ◽  
Progressive Ratio ◽  
Kappa Opioid Receptor ◽  
Sprague Dawley ◽  
Operant Responding ◽  
Mechanical Hypersensitivity ◽  
Weak Evidence ◽  
Preclinical Animal Models

Clinically relevant chronic pain is often associated with functional impairment and behavioral depression as an “affective/motivational” sign of pain; however preclinical animal models of inflammatory and neuropathic pain often produce weak evidence of impaired function. We hypothesized that hindpaw mechanical stimulation produced by a requirement to rear on a textured “NOX” plate would punish operant responding in rats treated with intraplantar complete Freund’s adjuvant (CFA, a model of inflammatory pain) or the chemotherapeutic paclitaxel (PTX, a model of neuropathic pain) and produce sustained pain-related depression of operant behavior. Male Sprague–Dawley rats were trained under a progressive-ratio (PR) schedule of food-maintained operant responding, then treated with CFA (100 µL in left hindpaw), PTX (2.0 mg/kg IP on alternate days for four total injections; 6.6 mg/kg IV on alternate days for three total injections), or saline vehicle. PR break points and mechanical thresholds for paw withdrawal from von Frey filaments were then tracked for 28 days. Subsequently, rats were tested with the opioid receptor antagonist naltrexone to assess latent sensitization and with the kappa opioid receptor (KOR) agonist U69593 to assess KOR function. CFA produced significant mechanical hypersensitivity for 3 weeks but decreased PR breakpoints for only 1 day. Both IP and IV PTX produced mechanical hypersensitivity for at least three weeks; however, only IV PTX decreased PR breakpoints, and this decrease was not alleviated by morphine. After recovery, naltrexone reinstated mechanical hypersensitivity in CFA- but not PTX-treated rats, and it did not reinstate depression of breakpoints in any group. U69593 dose-dependently decreased PR breakpoints in all groups with no difference between control vs. CFA/PTX groups. These results suggest that rearing on a textured NOX plate was not sufficient to punish operant responding in CFA- and PTX-treated rats despite the presence of sustained mechanical hypersensitivity. The rapid recovery of operant responding could not be attributed to latent sensitization, KOR downregulation, or behavioral tolerance. These results extend the range of conditions under which putative chronic pain manipulations produce weak evidence for depression of operant responding as a sign of the “affective/motivational” component of pain in rats.

scholarly journals Regular Exercise Reverses Sensory Hypersensitivity in a Rat Neuropathic Pain Model

2011 ◽  
Vol 114 (4) ◽  
pp. 940-948 ◽  
Author(s):  
Nicola J. Stagg ◽  
Heriberto P. Mata ◽  
Mohab M. Ibrahim ◽  
Erik J. Henriksen ◽  
Frank Porreca ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Exercise Training ◽  
Aerobic Exercise ◽  
Opioid Receptor ◽  
Endogenous Opioids ◽  
Receptor Antagonists ◽  
Endogenous Opioid ◽  
Sensory Hypersensitivity ◽  
Opioid Receptor Antagonists

Background Exercise is often prescribed as a therapy for chronic pain. Short-term exercise briefly increases the production of endogenous analgesics, leading to transient antinociception. In limited studies, exercise produced sustained increases in endogenous opioids, sustained analgesia, or diminished measures of chronic pain. This study tests the hypothesis that regular aerobic exercise leads to sustained reversal of neuropathic pain by activating endogenous opioid-mediated pain modulatory systems. Methods After baseline measurements, the L5 and L6 spinal nerves of male Sprague-Dawley rats were tightly ligated. Animals were randomized to sedentary or 5-week treadmill exercise-trained groups. Thermal and tactile sensitivities were assessed 23 h after exercise, using paw withdrawal thresholds to von Frey filaments and withdrawal latencies to noxious heat. Opioid receptor antagonists were administered by subcutaneous, intrathecal, or intracerebroventricular injection. Opioid peptides were quantified using immunohistochemistry with densitometry. Results Exercise training ameliorated thermal and tactile hypersensitivity in spinal nerve-ligated animals within 3 weeks. Sensory hypersensitivity returned 5 days after discontinuation of exercise training. The effects of exercise were reversed by using systemically or intracerebroventricularly administered opioid receptor antagonists and prevented by continuous infusion of naltrexone. Exercise increased β-endorphin and met-enkephalin content in the rostral ventromedial medulla and the mid-brain periaqueductal gray area. Conclusions Regular moderate aerobic exercise reversed signs of neuropathic pain and increased endogenous opioid content in brainstem regions important in pain modulation. Exercise effects were reversed by opioid receptor antagonists. These results suggest that exercise-induced reversal of neuropathic pain results from an up-regulation of endogenous opioids.

scholarly journals Investigating the antinociceptive effects of N-docosahexaenoyl ethanolamine and novel kappa opioid receptor agonists

2021 ◽  
Author(s):  
◽  
Kelly Paton
Keyword(s):  
Chronic Pain ◽  
Opioid Receptor ◽  
Mechanical Allodynia ◽  
Kappa Opioid Receptor ◽  
Nociceptive Pain ◽  
The Novel ◽  
Duration Of Action ◽  
Cold Allodynia ◽  
Antinociceptive Effects

<p>Chronic pain causes patients to endure prolonged suffering and discomfort, often having profound effects on quality of life. In New Zealand, one in five people currently suffer from chronic pain. To treat chronic pain, patients are typically prescribed drugs that activate the mu opioid receptor (MOPr), such as morphine, codeine and oxycodone. In recent years in the United States of America, there has been a rapid increase in the use of prescription and non-prescription opioid drugs, with opioid overdoses now the leading cause of accidental death. In New Zealand, daily doses of prescription opioids quadrupled in the ten year period from 2001-2011. Clearly, there is a need for the development of more effective and safe medications. This thesis evaluated two classes of non-addictive compounds: bioactive lipids and kappa opioid receptor (KOPr) agonists. N-docosahexaenoyl ethanolamine (DHEA) is an N-acyl ethanolamine class lipid that is structurally similar to the endocannabinoid anandamide. DHEA has previously been shown to have immune-modulatory effects in vitro, however, the in vivo effects have not previously been tested. Using the intraplantar 2% formaldehyde model in mice, DHEA reduced inflammatory and nociceptive pain via both intraperitoneal (i.p.) and local intraplantar (i.pl.) administration. DHEA significantly reduced formaldehyde-induced footpad oedema and reduced the infiltration of neutrophils into the inflamed tissue. The antinociceptive and anti-oedematous effects were not modulated by pre-treatment with either cannabinoid 1- or 2-type receptor antagonists. DHEA did not have any effect in a thermal nociceptive pain model and did not show any motor coordination impairment or changes in thermoregulation. In the search for non-addictive analgesics, KOPr agonists are a promising alternative. In contrast to MOPr agonists, KOPr agonists play a critical role in regulating the reward system. Salvinorin A (SalA) is a selective KOPr agonist that has antinociceptive and anti-inflammatory effects in vivo, with limited abuse potential. However, the short duration of action and aversive side effects limit the clinical usefulness. The present study aimed to investigate the antinociceptive effects of acute administration of novel analogues of SalA. In the dose-response tail withdrawal assay, SalA and the novel analogues 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail withdrawal assay and the hot plate test compared to SalA. In the intraplantar 2% formaldehyde test, SalA, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced nociceptive pain and inflammatory pain, effects which were reversed by the KOPr antagonist nor-binaltorphimine. SalA, 16-Ethynyl SalA and 16-Bromo SalA reduced paw oedema and reduced the infiltration of neutrophils into the inflamed tissue. However, SalA, 16-Ethynyl SalA and 16-Bromo SalA produced motor incoordination effects. However, 16-Ethynyl SalA did not alter thermoregulation. The KOPr agonists were further assessed in a model of paclitaxel-induced neuropathic pain. In the acute dose-response experiment, 16-Ethynyl SalA was significantly more potent at reducing mechanical allodynia compared to morphine in both male and female mice. SalA and 16-Ethynyl SalA were more potent at reducing cold allodynia than morphine. In a chronic administration model over 22 days, for the treatment of cold and mechanical allodynia, all of the opioid treatments reduced pain, however, the traditional KOPr agonist U50,488, was the most potent, by reducing the male mechanical allodynia and cold allodynia in both sexes back to baseline levels. The ultrastructure of the sciatic nerves were studied, however, it was found that U50,488 did not reverse the effects of paclitaxel on myelin degeneration and mitochondrial damage. Overall, this study has identified DHEA as a modest treatment for inflammatory pain, with reduced side effects and a mechanism of action in contrast to other compounds with a similar structure. The novel KOPr agonists had significant effects in acute pain models with longer duration of action than the parent compound SalA. This is the first known study to investigate the effects of KOPr agonists in a paclitaxel-induced neuropathic pain model, showing that KOPr agonists are a potential therapeutic avenue for this debilitating condition.</p>

scholarly journals Spinal Microglial Expression and Mechanical Hypersensitivity in a Postoperative Pain Model: Comparison with a Neuropathic Pain Model

2009 ◽  
Vol 111 (3) ◽  
pp. 640-648 ◽  
Author(s):  
Naomi Ito ◽  
Hideaki Obata ◽  
Shigeru Saito
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Postoperative Pain ◽  
Model Comparison ◽  
Kinase Inhibitor ◽  
Mitogen Activated Protein Kinase ◽  
Sprague Dawley ◽  
Pain Model ◽  
Mechanical Hypersensitivity ◽  
Neuropathic Pain Model

Background Postoperative pain control contributes to quality of life. Activation of spinal cord microglia after peripheral nerve injury contributes to mechanical hypersensitivity. The contribution of spinal cord microglia to hypersensitivity after surgery, however, is not well understood. Here, the authors evaluated whether inhibition of spinal microglia reduced postoperative mechanical hypersensitivity, and if so, whether the effect differed from that in a rat neuropathic pain model. Methods Male Sprague-Dawley rats underwent either unilateral plantar hind paw incision (postoperative pain model) or L5 spinal nerve transection (neuropathic pain model), and the development of mechanical hypersensitivity was assessed using von Frey filaments. The microglial inhibitor minocycline was intraperitoneally administered daily for either 3 or 7 days. Spinal microglial activation was evaluated by OX42 immunohistochemistry. We also tested the effect of intrathecal administration of a p38 mitogen-activated protein kinase inhibitor, SB203580. Results In the postoperative pain model, minocycline did not suppress mechanical hypersensitivity, but did inhibit an increase in spinal OX42 expression. In contrast, in the neuropathic pain model, minocycline reduced mechanical hypersensitivity in a dose-related manner and inhibited spinal OX42 expression. SB203580 attenuated hypersensitivity in the neuropathic pain model, but not in the postoperative pain model. Conclusions The results of the present study suggest that spinal OX42 expression has a more important role in the development of neuropathic pain than in postoperative pain, and that an increase in spinal OX42 expression does not contribute to postoperative mechanical hypersensitivity.

The kappa opioid receptor agonist SA14867 has antinociceptive and weak sedative effects in models of acute and chronic pain

2011 ◽  
Vol 671 (1-3) ◽  
pp. 53-60 ◽  
Author(s):  
Yaeko Tsukahara-Ohsumi ◽  
Fumio Tsuji ◽  
Masashi Niwa ◽  
Taeko Hata ◽  
Minoru Narita ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Opioid Receptor ◽  
Receptor Agonist ◽  
Kappa Opioid Receptor ◽  
Kappa Opioid ◽  
Opioid Receptor Agonist ◽  
Sedative Effects

scholarly journals Exploring the Aversive and Anxiogenic Effects of Novel Kappa Opioid Receptor Agonists in Rats

2021 ◽  
Author(s):  
◽  
Aimee Culverhouse
Keyword(s):  
Side Effects ◽  
Opioid Receptor ◽  
Kappa Opioid Receptor ◽  
Prime Model ◽  
The Novel ◽  
Negative Consequences ◽  
Sprague Dawley ◽  
Initial Attempt ◽  
Kappa Opioid ◽  
Duration Of Action

<p>Drug addiction is characterised by uncontrolled, compulsive drug use despite negative consequences. As this disease has a high social and economic cost, greater attention is required in finding an effective treatment for individuals suffering addiction. Kappa opioid receptor (KOPr) agonists demonstrate anti-addiction effects in the rodent cocaine drug-prime model of reinstatement. Salvinorin A (Sal A), a novel non-nitrogenous KOPr agonist, has demonstrated reduced side-effects compared to traditional agonists. However, its short half-life and duration of action limit clinical development. The design of novel Sal A analogues with improved pharmacokinetics, anti-addiction effects, and reduced side-effects is an important step towards the pharmaceutical development of KOPr agonists. β-Tetrahydropyran Sal B (β-THP Sal B), Mesyl Sal B, ethoxymethyl salvinorin B ether (EOM Sal B), and Ethynyl Sal A (Ethy Sal A) have demonstrated anti-addiction effects by reducing cocaine-seeking behaviour in rats, but their aversive and anxiogenic properties have yet to be examined. Here the conditioned place aversion (CPA) paradigm is used to evaluate aversion and the elevated plus maze (EPM), light/dark test, and open field are utilised to measure anxiety in male Sprague-Dawley rats.  EOM Sal B (0.1 mg/kg, i.p) and Ethy Sal A (0.3 mg/kg, i.p) did not produce aversive effects, whereas the traditional KOPr agonist U50,488 (10 mg/kg, i.p), Sal A (0.3 mg/kg, i.p), and the novel analogue β-THP Sal B (1 mg/kg, i.p) produced significant aversion using the CPA protocol.  In the EPM all the novel analogues, β-THP Sal B, EOM Sal B, Mesyl Sal B, and Ethy Sal, A did not show a reduction in time spent on the open arm. In addition, EOM Sal B showed a significant increase in time spent on the open arm compared with Sal A (0.3 mg/kg, i.p). Sal A (0.3 and 1 mg/kg, i.p) showed significant anxiogenic effects, but the traditional agonist U50,488 did not. In the light/dark test Sal A (1 mg/kg, i.p) showed significant dose dependent anxiogenic effects with significant effects observed at 1 but not 0.3 mg/kg dose. This is in contrast to results observed in the EPM. The novel analogues EOM Sal B and β-THP Sal B demonstrated a non-significant trend toward anxiogenic behaviour in the light/dark test, but U50,488, Mesyl Sal B, and Ethy Sal A did not show significant reductions in time spent in the light box.  KOPr stimulation activates its associated G-proteins, allowing them to interact with several intracellular effectors. Activation of cAMP response element binding protein (CREB) can occur downstream of the KOPr signalling cascade. The phosphorylation of CREB is associated with dysphoria and stress-induced reinstatement of drug-seeking behaviour. An initial attempt to validate CREB assays was made.  The lack of behavioural anxiogenic and aversive side-effects with EOM Sal B, Mesyl Sal B and Ethy Sal A treatment demonstrates that the development of KOPr agonists with desirable effects and reduced side-effects is possible. These novel Sal A agonists provide promising candidates for pharmacotherapy development.</p>

Coexisting mechanical hypersensitivity and anxiety in a rat model of spinal cord injury and the effect of pregabalin, morphine, and midazolam treatment

2011 ◽  
Vol 2 (3) ◽  
pp. 139-145 ◽  
Author(s):  
Cathrine Baastrup ◽  
Troels S. Jensen ◽  
Nanna B. Finnerup
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Neuropathic Pain ◽  
Anxiety And Depression ◽  
Preclinical Model ◽  
Sprague Dawley ◽  
Mechanical Hypersensitivity ◽  
Anxiolytic Drug ◽  
Cord Injury ◽  
Spinal Cord Contusion

AbstractBackground and purposeSpinal cord injury (SCI) has detrimental consequences that include chronic neuropathic pain, which is seen in 40-50% of patients, and symptoms of anxiety and depression, which affect 13-45% of SCI patients. The coexistence of pain, anxiety, and depression is known from other neuropathic pain conditions, but the relationship between these symptoms is not clear and has not been investigated in a preclinical model of SCI so far.The aim of this study was to investigate anxiety-like behavior and at-level mechanical hypersensitivity following experimental spinal cord contusion (SCC) in female Sprague-Dawley rats, and the effects of analgesic and anxiolytic drugs.MethodsMechanical sensitivity and elevated plus maze (EPM) behavior were measured pre- and postinjury in SCC and sham animals. Pregabalin 30 mg/kg, morphine 3 mg/kg, midazolam 0.5 mg/kg, and 0.9% NaCl were evaluated in a randomly allocated, blinded balanced design.ResultsSCC animals developed persistent at-level mechanical hypersensitivity and decreased open arm activity in the EPM, which indicates an anxiety-like state. Pregabalin, a dual-acting analgesic and anxiolytic drug reduced both hypersensitivity and anxiety-like behavior, while the analgesic drug morphine only reduced hypersensitivity. The anxiolytic drug midazolam in the dose used had no effect on either parameter.ConclusionsSCC animals developed long lasting coexisting at-level mechanical hypersensitivity and anxiety-like behavior, but there was no evidence to support a causal relationship between pain and anxiety following SCI.ImplicationsThe findings that at-level mechanical hypersensitivity and anxiety-like behavior develops concomitantly in the spinal cord contusion models and that both symptoms is persistent provide basis for further investigation of the mechanisms and connection behind these two clinically relevant symptoms after injury to the central nervous system.

scholarly journals Investigating the antinociceptive effects of N-docosahexaenoyl ethanolamine and novel kappa opioid receptor agonists

2021 ◽  
Author(s):  
◽  
Kelly Paton
Keyword(s):  
Chronic Pain ◽  
Opioid Receptor ◽  
Mechanical Allodynia ◽  
Kappa Opioid Receptor ◽  
Nociceptive Pain ◽  
The Novel ◽  
Duration Of Action ◽  
Cold Allodynia ◽  
Antinociceptive Effects

<p>Chronic pain causes patients to endure prolonged suffering and discomfort, often having profound effects on quality of life. In New Zealand, one in five people currently suffer from chronic pain. To treat chronic pain, patients are typically prescribed drugs that activate the mu opioid receptor (MOPr), such as morphine, codeine and oxycodone. In recent years in the United States of America, there has been a rapid increase in the use of prescription and non-prescription opioid drugs, with opioid overdoses now the leading cause of accidental death. In New Zealand, daily doses of prescription opioids quadrupled in the ten year period from 2001-2011. Clearly, there is a need for the development of more effective and safe medications. This thesis evaluated two classes of non-addictive compounds: bioactive lipids and kappa opioid receptor (KOPr) agonists. N-docosahexaenoyl ethanolamine (DHEA) is an N-acyl ethanolamine class lipid that is structurally similar to the endocannabinoid anandamide. DHEA has previously been shown to have immune-modulatory effects in vitro, however, the in vivo effects have not previously been tested. Using the intraplantar 2% formaldehyde model in mice, DHEA reduced inflammatory and nociceptive pain via both intraperitoneal (i.p.) and local intraplantar (i.pl.) administration. DHEA significantly reduced formaldehyde-induced footpad oedema and reduced the infiltration of neutrophils into the inflamed tissue. The antinociceptive and anti-oedematous effects were not modulated by pre-treatment with either cannabinoid 1- or 2-type receptor antagonists. DHEA did not have any effect in a thermal nociceptive pain model and did not show any motor coordination impairment or changes in thermoregulation. In the search for non-addictive analgesics, KOPr agonists are a promising alternative. In contrast to MOPr agonists, KOPr agonists play a critical role in regulating the reward system. Salvinorin A (SalA) is a selective KOPr agonist that has antinociceptive and anti-inflammatory effects in vivo, with limited abuse potential. However, the short duration of action and aversive side effects limit the clinical usefulness. The present study aimed to investigate the antinociceptive effects of acute administration of novel analogues of SalA. In the dose-response tail withdrawal assay, SalA and the novel analogues 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail withdrawal assay and the hot plate test compared to SalA. In the intraplantar 2% formaldehyde test, SalA, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced nociceptive pain and inflammatory pain, effects which were reversed by the KOPr antagonist nor-binaltorphimine. SalA, 16-Ethynyl SalA and 16-Bromo SalA reduced paw oedema and reduced the infiltration of neutrophils into the inflamed tissue. However, SalA, 16-Ethynyl SalA and 16-Bromo SalA produced motor incoordination effects. However, 16-Ethynyl SalA did not alter thermoregulation. The KOPr agonists were further assessed in a model of paclitaxel-induced neuropathic pain. In the acute dose-response experiment, 16-Ethynyl SalA was significantly more potent at reducing mechanical allodynia compared to morphine in both male and female mice. SalA and 16-Ethynyl SalA were more potent at reducing cold allodynia than morphine. In a chronic administration model over 22 days, for the treatment of cold and mechanical allodynia, all of the opioid treatments reduced pain, however, the traditional KOPr agonist U50,488, was the most potent, by reducing the male mechanical allodynia and cold allodynia in both sexes back to baseline levels. The ultrastructure of the sciatic nerves were studied, however, it was found that U50,488 did not reverse the effects of paclitaxel on myelin degeneration and mitochondrial damage. Overall, this study has identified DHEA as a modest treatment for inflammatory pain, with reduced side effects and a mechanism of action in contrast to other compounds with a similar structure. The novel KOPr agonists had significant effects in acute pain models with longer duration of action than the parent compound SalA. This is the first known study to investigate the effects of KOPr agonists in a paclitaxel-induced neuropathic pain model, showing that KOPr agonists are a potential therapeutic avenue for this debilitating condition.</p>

scholarly journals Glucagon-Like Peptide-1 (GLP-1) and 5-Hydroxytryptamine 2c (5-HT2c) Receptor Agonists in the Ventral Tegmental Area (VTA) Inhibit Ghrelin-Stimulated Appetitive Reward

2019 ◽  
Vol 20 (4) ◽  
pp. 889 ◽  
Author(s):  
Erin Howell ◽  
Hannah Baumgartner ◽  
Lia Zallar ◽  
Joaquín Selva ◽  
Liv Engel ◽  
...  
Keyword(s):  
Ventral Tegmental Area ◽  
Receptor Agonist ◽  
Food Reinforcement ◽  
Progressive Ratio ◽  
Sprague Dawley ◽  
Operant Responding ◽  
Orexigenic Peptide ◽  
Glucagon Like Peptide ◽  
Ventral Tegmental ◽  
Glucagon Like Peptide 1

Current literature indicates that the orexigenic peptide ghrelin increases appetitive motivation via signaling in the mesolimbic reward system. Another gastric peptide, glucagon-like peptide-1 (GLP-1), and the neurotransmitter 5-hydroxytryptamine (5-HT), are both known to suppress operant responding for food by acting on key mesolimbic nuclei, including the ventral tegmental area (VTA). In order to investigate the interaction effects of ghrelin, GLP-1, and 5-HT within the VTA, we measured operant responding for sucrose pellets after the administration of ghrelin, the GLP-1 receptor agonist exendin-4 (Ex-4), and the 5-HT2c receptor agonist Ro60-0175 in male Sprague-Dawley rats. Following training on a progressive ratio 3 (PR3) schedule, animals were first injected with ghrelin into the VTA at doses of 3 to 300 pmol. In subsequent testing, separate rats were administered intraperitoneal (IP) Ex-4 (0.1–1.0 µg/kg) or VTA Ex-4 (0.01–0.1 µg) paired with 300 pmol ghrelin. In a final group of rats, the 5-HT2c agonist Ro60-0175 was injected IP (0.25–1.0 mg/kg) or into the VTA (1.5–3.0 µg), and under both conditions paired with 300 pmol ghrelin delivered into the VTA. Our results indicated that ghrelin administration increased operant responding for food reward and that this effect was attenuated by IP and VTA Ex-4 pretreatment as well as pre-administration of IP or VTA Ro60-0175. These data provide compelling evidence that mesolimbic GLP-1 and serotonergic circuitry interact with the ghrelinergic system to suppress ghrelin’s effects on the mediation of food reinforcement.

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