Morphine-induced Conditioned Place Preference Research Articles

S-3,4-DCPG, a potent orthosteric agonist for the mGlu8 receptor, facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats

The limbic system, particularly the NAc, shows a high concentration of metabotropic glutamate receptors (mGluRs). Recent evidence suggests the significant involvement of mGluRs in mental disorders, including substance abuse and addiction. The objective of this study was to examine the involvement of mGlu8 receptors in the NAc in the mechanisms underlying the extinction and reinstatement of conditioned place preference (CPP) induced by morphine. Male Wistar rats underwent surgical implantation of bilateral cannulas in the NAc and were assessed in a CPP protocol. In study 1 at the same time as the extinction phase, the rats were given varying doses of S-3,4-DCPG (0.03, 0.3, and 3 μg/0.5 μl). In study 2, rats that had undergone CPP extinction were given S-3,4-DCPG (0.03, 0.3, and 3 μg/0.5 μl) five minutes prior to receiving a subthreshold dose of morphine (1 mg/kg) in order to reactivate the previously extinguished morphine response. The findings demonstrated that administering S-3,4-DCPG directly into the accumbens nucleus resulted in a decrease in the duration of the CPP extinction phase. Moreover, dose-dependent administration of S-3,4-DCPG into the NAc inhibited CPP reinstatement. The observations imply that microinjection of S-3,4-DCPG as a potent orthosteric agonist with high selectivity for the mGlu8 receptor into the NAc promotes the process of extinction while concurrently exerting inhibitory effects on the reinstatement of morphine-induced CPP. This effect may be associated with the modulation of glutamate engagement within the NAc and the plasticity of reward pathways at the synaptic level.

N-acetylcysteine attenuates accumbal core neuronal activity in response to morphine in the reinstatement of morphine CPP in morphine extinguished rats

Numerous studies have suggested that N-acetylcysteine (NAC), has the potential to suppress drug craving in people with substance use disorder and reduce drug-seeking behaviors in animals. The nucleus accumbens (NAc) plays a crucial role in the brain's reward system, with the nucleus accumbens core (NAcore) specifically implicated in compulsive drug seeking and relapse. In this study, we aimed to explore the impact of subchronic NAC administration during the extinction period and acute NAC administration on the electrical activity of NAcore neurons in response to a priming dose of morphine in rats subjected to extinction from morphine-induced place preference (CPP).We conducted single-unit recordings in anesthetized rats on the reinstatement day, following the establishment of morphine-induced conditioned place preference (7 mg/kg, s.c., 3 days), and subsequent drug-free extinction. In the subchronically NAC-treated groups, rats received daily injections of either NAC (50 mg/kg; i.p.) or saline during the extinction period. On the reinstatement day, we recorded the spontaneous activity of NAcore neurons for 15 min, administered a priming dose of morphine, and continued recording for an additional 45 min. While morphine excited most recorded neurons in saline-treated rats, it failed to alter firing rates in NAC-treated rats that had received NAC during the extinction period. For acutely NAC-treated animals, we recorded the baseline activity of NAcore neurons for 10 min before administering a single injection of either NAC (50 mg/kg; i.p.) or saline in rats with no treatment during the extinction. Following 30 min of recording and a priming dose of morphine (1 mg/kg, s.c.), the recording continued for an additional 30 min. The firing activity of NAcore neurons did not show significant changes after morphine or NAC injection. In conclusion, our findings emphasize that daily NAC administration during the extinction period significantly attenuates the morphine-induced increase in firing rates of NAcore neurons during the reinstatement of morphine CPP. However, acute NAC injection does not produce the same effect. These results suggest that modulating glutamate transmission through daily NAC during extinction may effectively inhibit the morphine place preference following the excitatory effects of morphine on NAcore neurons.

A novel dopamine D2 receptor-NR2B protein complex might contribute to morphine use disorders

Dopamine receptors can form heteromeric interactions with other receptors, including glutamate receptors, and present a novel pharmacological target because it contribute to dopamine-dysregulated brain disorders such as addiction and other motor-related diseases. In addition, dopamine receptors D2 (D2Rs) and glutamate NMDA receptors subtype-NR2B have been implicated in morphine use disorders; however, the molecular mechanism underlying the heteromeric complex of these two receptors in morphine use disorders is unclear. Herein, we focus on interactions between D2R and NR2B in morphine-induced conditioned place preference (CPP) and hyperlocomotion mice models. We found that the D2R–NR2B complex significantly increases in morphine-induced mice models, accompanied by ERK signaling impairment, implying the complex could contribute to the morphine addiction pathophysiological process. Further, we design a brain-penetrant interfering peptide (TAT-D2-KT), which could disrupt interactions of D2R–NR2B and decrease addictive-like behaviors concurrent to ERK signaling improvement. In summary, our data provided the first evidence for a D2R-NMDAR complex formation in morphine use disorders and its underlying mechanism of ERK signaling, which could present a novel therapeutic target with direct implications for morphine acquisition and relapse treatment.

Effects of Hydro-Alcoholic Extract of Salvia Officinalis L. on the Acquisition and Expression of Morphine-Induced Conditioned Place Preference in Mice: An Experimental Study

Effects of Hydro-Alcoholic Extract of Salvia Officinalis L. on the Acquisition and Expression of Morphine-Induced Conditioned Place Preference in Mice: An Experimental Study

Effects of the novel selective κ-opioid receptor agonist NP-5497-KA on morphine-induced reward-related behaviors

Opioid addiction and the opioid overdose epidemic are becoming more serious, and the development of therapeutic agents is essential for the pharmacological treatment of substance use disorders. The κ-opioid receptor (KOP) is a member of the opioid receptor system that has been gaining attention as a promising molecular target for the treatment of numerous human disorders, including pain, depression, anxiety, and drug addiction. Here, we biologically and pharmacologically evaluated a novel azepane-derived ligand, NP-5497-KA, as a selective KOP agonist. NP-5497-KA had 1000-fold higher selectivity for the KOP over the μ-opioid receptor (MOP), which was higher than nalfurafine (KOP/MOP: 65-fold), and acted as a selective KOP full agonist in the 3′,5′-cyclic adenosine monophosphate assay. The oral administration of NP-5497-KA (1–10 mg/kg) dose-dependently suppressed morphine-induced conditioned place preference in C57BL/6 J mice, and its effects were comparable to an intraperitoneal injection of nalfurafine (1–10 μg/kg). Nalfurafine (10 μg/kg) significantly inhibited rotarod performance, whereas NP-5497-KA (10 mg/kg) exerted no effect on rotarod performance. These results indicate that NP-5497-KA may be a novel option for the treatment of opioid use disorder with fewer side effects.

The α1 adrenoceptor antagonist prazosin potentiates morphine induced conditioned place preference in rats

The norepinephrine (NE) system is involved in pathways that regulate morphine addiction. Here, we investigated the role of α1 adrenoceptor in the ventrolateral orbital cortex (VLO) of rats with repeated morphine treatment and underlying molecular mechanisms. The rewarding properties of morphine were assessed by the conditioned place preference (CPP) paradigm. Prazosin, an α1 adrenoceptor antagonist, was microinjected into the VLO. The expression of α1 adrenoceptor, p-CaMKII/CaMKII, CRTC1, BDNF and PSD95 in the VLO were determined by immunohistochemistry or western blotting. Neurotransmitter NE in the VLO and inflammatory factors in serum were detected separately through high-performance liquid chromatography and enzyme-linked immunosorbent assay. Our experimental results showed that repeated morphine administration induced stable CPP and prazosin promoted the morphine-induced CPP. Microinjection of prazosin in the VLO not only blocked the activity of α1 adrenoceptor, decreased CaMKII phosphorylation and CRTC1, which eventually resulted in a regression of synaptic plasticity-related proteins, but also was accompanied by significantly decreasing of NE in the VLO and increasing of inflammatory cytokines in peripheral blood. These findings suggested that prazosin potentiates the addictive effects of morphine. The effect of increased CPP through reducing α1 adrenoceptor and NE was associated with the CaMKII-CRTC1 pathway and synaptic plasticity-related proteins in the VLO and inflammatory cytokines in the peripheral blood. The NE system may therefore be an underlying therapeutic target in morphine addiction. Additionally, we believe that the clinical use of prazosin in hypertensive patients with morphine abuse may be a potential risk because of its reinforcing effect on addiction.

Postpartum scarcity-adversity inflicts sex-specific cerebellar adaptations and reward behaviors in adolescence

Early life adversity in the form of poor postnatal care is a major developmental stressor impacting behavior later in life. Previous studies have shown the impact of early life stress on neurobehavioral abnormalities. Specifically, research has demonstrated how limited bedding and nesting (LBN) materials can cause behavioral deficits in adulthood. There is, however, a limited understanding of how LBN influences sex-specific neurobehavioral adaptation in adolescence, a developmental stage susceptible to psychiatric diseases including substance use disorder. LBN and stress-naive c57BL/6 adolescent male and female mouse offspring were tested for a battery of behaviors including open field, novel object recognition, elevated plus maze, social preference, and morphine-induced conditioned place preference. There was a significant sex-specific deficit in social preference in male mice exposed to LBN compared to stress-naïve counterparts and both LBN males and females had a higher preference towards the drug-paired chamber in the morphine-induced conditioned place preference test. These behavioral deficits were concomitant with sex-specific increases in the transcription factor, Klf9 in the deep cerebellar nuclei (DCN) of males. Further, mRNA levels of the circadian gene Bmal1, which is known to be transcriptionally regulated by Klf9, were decreased in the DCN. Since Bmal1 has recently been implicated in extracellular matrix modulation, we examined perineuronal nets (PNN) and observed depleted PNN in the DCN of males but not female LBN mice. Overall, we provide a novel understanding of how postpartum adversity impinges on the cerebellar extracellular matrix homeostasis, likely, through disruption of the circadian axis by Klf9 that might underlie sex-specific behavioral adaptations in adolescence.

Nicotine limits avoidance conditioning with opioids without interfering with the ability to discriminate an opioid-interoceptive state

Approximately 90 % of individuals undergoing treatment for opioid use disorder (OUD) report comorbid use of nicotine. As such, further investigation into underlying mechanisms contributing to the extreme comorbidity between nicotine and opioid use are warranted. Nicotine administration significantly escalates self-administration of opioids and this increase in motivational efficacy persists despite contingent punishment of opioid consumption. Additionally, both systemic and intra-insular administration of nicotine produces a rightward shift in the dose-response function in both morphine-induced conditioned place preference and taste avoidance paradigms, particularly at higher doses (5–20 mg/kg). Two possible interpretations arise from these outcomes. One is that nicotine may specifically affect learning about the malaise-inducing effects of morphine thus facilitating acceptance of higher doses of morphine. Another interpretation is that it more generally reduces sensitivity to the interoceptive effects of morphine such that higher doses are needed to produce comparable effects in nicotine-treated, relative to control, rats. To further address these possibilities, we asked whether nicotine administration interfered with the ability to discriminate the morphine interoceptive state, irrespective of its hedonic evaluation, at a dose that is impacted by nicotine in avoidance conditioning paradigms. First, we demonstrated that systemic nicotine pretreatment significantly attenuates taste avoidance induced by a low dose of morphine (3 mg/kg). Next, we used an occasion setting paradigm with this same dose of morphine to test whether systemic nicotine pretreatment interferes with the ability to discriminate between saline- and morphine-induced interoceptive states. Within this task, nicotine had no effect on the ability to effectively discriminate between the interoceptive effects of morphine and saline. Collectively, these data suggest that nicotine may be specifically altering the overall hedonic assessment of morphine perhaps by interfering with learning about its deleterious consequences.

Loss of Astrocytic µ Opioid Receptors Exacerbates Aversion Associated with Morphine Withdrawal in Mice: Role of Mitochondrial Respiration.

Astrocytes express mu/µ opioid receptors, but the function of these receptors remains poorly understood. We evaluated the effects of astrocyte-restricted knockout of µ opioid receptors on reward- and aversion-associated behaviors in mice chronically exposed to morphine. Specifically, one of the floxed alleles of the Oprm1 gene encoding µ opioid receptor 1 was selectively deleted from brain astrocytes in Oprm1 inducible conditional knockout (icKO) mice. These mice did not exhibit changes in locomotor activity, anxiety, or novel object recognition, or in their responses to the acute analgesic effects of morphine. Oprm1 icKO mice displayed increased locomotor activity in response to acute morphine administration but unaltered locomotor sensitization. Oprm1 icKO mice showed normal morphine-induced conditioned place preference but exhibited stronger conditioned place aversion associated with naloxone-precipitated morphine withdrawal. Notably, elevated conditioned place aversion lasted up to 6 weeks in Oprm1 icKO mice. Astrocytes isolated from the brains of Oprm1 icKO mice had unchanged levels of glycolysis but had elevated oxidative phosphorylation. The basal augmentation of oxidative phosphorylation in Oprm1 icKO mice was further exacerbated by naloxone-precipitated withdrawal from morphine and, similar to that for conditioned place aversion, was still present 6 weeks later. Our findings suggest that µ opioid receptors in astrocytes are linked to oxidative phosphorylation and they contribute to long-term changes associated with opioid withdrawal.

The role of NMDA glutamate receptors in the lateral habenula on morphine-induced conditioned place preference in rats.

The lateral habenula (LHb) has received special attention due to its role in modulating motivated behavior, stress response, and rewarding and aversive stimuli through monoamine transmission. In the present study, the involvement of the N-methyl-d-aspartate (NMDA) receptors of the LHb in the expression and acquisition phases of morphine-induced conditioned place preference (CPP) was studied in male rats. Bilateral injections of agonist/antagonist (MK-801) of NMDA receptor were performed during the conditioning sessions of the acquisition phase. In other separate groups, drugs were also injected into the LHb before the test session during the expression phase of CPP. A 5-day CPP bias paradigm was used to study the effect of injections of NMDA and MK-801 into the LHb on morphine reward-related behavior. Different doses of NMDA plus morphine reduced the CPP score during the acquisition phase, whereas MK-801 significantly increased conditioning scores during the acquisition phase of CPP. The injection of agonists and antagonists of NMDA receptors in LHb had no significant effect on CPP scores and locomotion during the expression phase of CPP, whereas the motor activity in the acquisition phase was affected by the drugs. The reduction effect of NMDA on the CPP scores during the acquisition phase was blocked by pretreatment with MK-801. Our findings also suggest that NMDA receptors in the LHb may be involved in the acquisition phase of morphine-induced CPP.

The blockade of orexin receptors within the dentate gyrus of the hippocampus attenuated methamphetamine-induced reward learning during conditioning place preference

Orexins and orexinergic receptors have been shown to play a critical role in reward processing and drug addiction. Previous studies showed that the orexinergic system in the dentate gyrus (DG) region of the hippocampus affects the conditioning (acquisition) and post-conditioning (expression) phases of morphine-induced conditioned place preference (CPP). The action of each orexin receptor within the DG during conditioning and expression phases for methamphetamine (METH)-induced CPP remains unclear. The present study aimed to determine the role of orexin-1 and -2 receptors in the hippocampal DG in METH CPP acquisition and expression. During the 5-day conditioning phase, rats received an intra-DG microinjection of SB334867, a selective orexin-1 receptor (OX1R) antagonist, or TCS OX2-29, a selective orexin-2 receptor (OX2R) antagonist, before injection of METH (1 mg/kg; sc). In different sets of animals on the expression day, rats received each antagonist before the CPP test. The results showed that SB334867 (3, 10, and 30 nmol) and TCS OX2-29 (3, 10, and 30 nmol) significantly decreased the acquisition of METH CPP during the conditioning phase. Furthermore, administration of SB 334867 (10 and 30 nmol) and TCS OX2-29 (3 and 10 nmol) on the post-conditioning day significantly reduced METH-induced CPP expression. The results also indicated that orexin receptors play a more critical role in the conditioning phase than in the expression phase. In summary, the orexin receptors in the DG play a crucial role in drug learning and memory and are essential for METH reward acquisition and expression.

Effect of risperidone on morphine-induced conditioned place preference and dopamine receptor D2 gene expression in male rat hippocampus.

Previous studies suggest the possible effect of risperidone on brain reward system and D1 and D2 dopamine receptors' involvement in morphine-induced conditioned place preference (CPP). The present study was designed to investigate the effect of risperidone as an atypical antipsychotic drug on morphine-induced CPP and D2-like dopamine receptor gene expression in rat. An unbiased CPP paradigm was used to study the effect of risperidone. Intraperitoneal (i.p.) injection of risperidone (1, 2, and 4mg/kg) was performed 30min before the morphine (10mg/kg, i.p.) injection and just after the rat was placed in the CPP box. The open field test was used to assay the locomotor activity of animal. The gene expression of D2 dopamine receptor in hippocampus was measured by real-time PCR technique. The hippocampi of rats were also used for histology evaluation. Morphine-produced (10mg/kg) CPP and morphine-induced CPP were reversed only by the administration of a low dose of risperidone (1mg/kg). Low dose of risperidone (1mg/kg) showed no effect on locomotor activity but a higher dose of risperidone (2 and 4mg/kg) decreased locomotor activity. Real-time PCR data analysis revealed that the gene expression of D2 dopamine receptor had significant difference between morphine and a 1mg/kg dose of risperidone. Moreover, in histological evaluation, apoptosis was observed in the morphine group, whereas there was no evidence of apoptosis in the risperidone-treated groups. Our results suggest that risperidone (1mg/kg) reverses the morphine-induced CPP and may reduce the rewarding properties of morphine. It is also demonstrated that risperidone decreases the expression of D2 receptor in rat hippocampus. Therefore, risperidone can be considered potential adjunct therapy in morphine dependence.

Brain glucose metabolism and dopamine transporter changes in rats with morphine-induced conditioned place preference.

Addiction to morphine is a chronic brain disease leading to compulsive abuse. Drug addiction animal models with and without conditioned place preference (CPP) training have been used to investigate cue-elicited drug craving. We used 18 F-fluorodeoxyglucose (18 F-FDG) and 11 C-2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane (11 C-CFT) micro-PET/CT scans to examine the regional changes in brain glucose metabolism and dopamine transporter (DAT) availability to study their relationship underlying drug memory in morphine-treated rat models with and without CPP. Standardized uptake value ratio (SUVr) of 18 F-FDG significantly decreased in the medial prefrontal cortex (mPFC) and cingulate with short-term morphine administration compared with the baseline condition. Voxelwise analysis indicated glucose metabolism alterations in the somatosensory cortex, hippocampus and cingulate in morphine-treated rats and in the striatum, thalamus, medial prefrontal cortex, primary motor cortex and many regions in the cortex in the CPP group compared with the baseline condition. Alterative glucose metabolism was also observed in the striatum, primary somatosensory cortex and some cortical regions in the CPP group compared with morphine alone group. DAT expression alterations were only observed in the long-term morphine compared with the short-term morphine group. This study shows that cerebral glucose metabolism significantly altered during morphine administration and CPP process mainly in the mPFC, striatum and hippocampus, which indicates that the function of these brain regions is involved in cue-induced craving and memory retrieval.

VU0155041, a positive allosteric modulator of mGluR4, in the nucleus accumbens facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats

Nucleus accumbens (NAc) neurons appear to be at the hub of the reward circuit. New evidence suggests that the behavioural effects of morphine substances may be significantly regulated by glutamate-mediated transmission, notably by metabotropic glutamate (mGlu) receptors. Here, we examined the hypothesis that the mGlu4 receptor within that NAc has a role in the extinction and reinstatement of morphine-induced conditioned place preference (CPP). The animals received bilaterally microinjections of VU0155041, a positive allosteric modulator (PAM) and partial agonist of mGlu4 receptor, into the NAc. In Experiment 1, the rats received VU0155041 (10, 30 and 50 μg/0.5 μL) during the extinction period. In Experiment 2, the CPP extinguished rats received VU0155041 (10, 30 and 50 μg/0.5 μL) five minutes prior to the administration of morphine (1 mg/kg) in order to reinstate the extinguished CPP. The results showed that the intra-accumbal administration of VU0155041 reduced the extinction period of CPP. Furthermore, the administration of VU0155041 into the NAc dose-dependently inhibited the reinstatement of CPP. The findings suggested that the mGluR4 in the NAc facilitates the extinction and inhibits the reinstatement of the morphine-induced CPP, which could be mediated by an increase in the release of extracellular glutamate.

Evaluation of the effect of mesenchymal stem cells injection in the nucleus accumbens on the morphine reinstatement behavior in a conditioned place preference model in Wistar rat: Expression changes of NMDA receptor subunits and NT-3

Mesenchymal stem cells (MSCs) have been recently shown to improve functional recovery in animal models of CNS disorders and are currently being examined in clinical studies for sclerosis, stroke, and CNS lesions. The activation of endogenous CNS protection and repair mechanisms is unclear. MSC-based approaches are considered a new potential target for neurodegenerative disorders. This study was designed to discover the effect of MSCs injection in the nucleus accumbens (NAc) on the reinstatement of behavior in morphine-induced conditioned place preference (CPP) in male rats. The CPP was induced via intra-peritoneal (i.p.) morphine injection (5 mg/kg) for three consecutive days. After being tested for CPP induction, animals received MSCs or culture medium (DMEM F-12) in their NAc using stereotaxic surgery. Following extinction, a priming dose of morphine (2 mg/kg) was administered to induce reinstatement. Expression of GluN1, GluN2A, and GluN2B subunits of the NMDA receptor and the NT-3 gene in the NAc was assessed on the last day of extinction and following CPP reinstatement. The results showed that local injection of MSCs attenuated reinstatement after receiving a priming dose of morphine, and also shortened the period of CPP extinction. The mRNA expression of the NT-3 gene in the group receiving MSCs was increased compared to control animals, as was observed for GluN1 and GluN2B, but not GluN2A. It is concluded that intra-NAc injection of MSCs may facilitate morphine extinction and alleviate reinstatement behavior which may be via expression changes in NMDA receptor subunits and NT-3 gene.

Inhibitory Effects of a Novel μ-Opioid Receptor Nonpeptide Antagonist, UD-030, on Morphine-Induced Conditioned Place Preference

Although opioids are widely used to treat moderate to severe pain, opioid addiction and the opioid overdose epidemic are becoming more serious. Although opioid receptor antagonists/partial agonists, such as naltrexone and buprenorphine, have relatively low selectivity for the μ-opioid receptor (MOP), they have been used for the management of opioid use disorder. The utility of highly selective MOP antagonists remains to be evaluated. Here, we biologically and pharmacologically evaluated a novel nonpeptide ligand, UD-030, as a selective MOP antagonist. UD-030 had more than 100-fold higher binding affinity for the human MOP (Ki = 3.1 nM) than for δ-opioid, κ-opioid, and nociceptin receptors (Ki = 1800, 460, and 1800 nM, respectively) in competitive binding assays. The [35S]-GTPγS binding assay showed that UD-030 acts as a selective MOP full antagonist. The oral administration of UD-030 dose-dependently suppressed the acquisition and expression of morphine-induced conditioned place preference in C57BL/6J mice, and its effects were comparable to naltrexone. These results indicate the UD-030 may be a new candidate for the treatment of opioid use disorder, with characteristics that differ from traditional medications that are in clinical use.

The electrical stimulation of the central nucleus of the amygdala in combination with dopamine receptor antagonist reduces the acquisition phase of morphine-induced conditioned place preference in male rat.

The central nucleus of the amygdala (CeA) is one of the nuclei involved in the reward system. The aim of the current study was to investigate the electrical stimulation (e-stim) effect of the CeA in combination with dopamine D1 receptor antagonist on morphine-induced conditioned place preference (CPP) in male rats. A 5-day procedure of CPP was used in this study. Morphine was administered at an effective dose of 5 mg/kg, and SCH23390 as a selective D1 receptor antagonist was administrated into the CeA. In addition, the CeA was stimulated with an intensity of the current of 150 μA. Finally, the dependence on morphine was evaluated in all experimental groups. Morphine significantly increased CPP. While the blockade of the D1 receptor of the CeA reduced the acquisition phase of morphine-induced CPP. Moreover, the combination of D1 receptor antagonist and e-stim suppressed morphine-induced CPP, even it induced an aversion. The current study suggests that the administration of dopamine D1 receptor antagonist into the CeA in combination with e-stim could play a prominent role in morphine dependence.

The reinstatement of the expression phase of morphine-induced conditioned place preference in male Wistar rats under ventral tegmental area stimulation and brief inactivation

The reinstatement of the expression phase of morphine-induced conditioned place preference in male Wistar rats under ventral tegmental area stimulation and brief inactivation

High-CBD Cannabis Vapor Attenuates Opioid Reward and Partially Modulates Nociception in Female Rats

Chronic pain patients report analgesic effects when using cannabidiol (CBD), a phytocannabinoid found in whole-plant cannabis extract (WPE). Several studies suggest that cannabis-derived products may serve as an analgesic adjunct or alternative to opioids, and importantly, CBD may also attenuate the abuse potential of opioids. Vaping is a popular route of administration among people who use cannabis, however both the therapeutic and hazardous effects of vaping are poorly characterized. Despite the fact that chronic pain is more prevalent in women, the ability of inhaled high-CBD WPE to relieve pain and reduce opioid reward has not been studied in females. Here, we present a comprehensive analysis of high-CBD WPE vapor inhalation in female rats. We found that WPE was modestly efficacious in reversing neuropathy-induced cold allodynia in rats with spared nerve injury (SNI). Chronic exposure to WPE did not affect lung cytoarchitecture or estrous cycle, and it did not induce cognitive impairment, social withdrawal or anxiolytic effects. WPE inhalation prevented morphine-induced conditioned place preference and reinstatement. Similarly, WPE exposure reduced fentanyl self-administration in rats with and without neuropathic pain. We also found that WPE vapor lacks of reinforcing effects compared to the standard excipient used in most vapor administration research. Combined, these results suggest that although high-CBD vapor has modest analgesic effects, it has a robust safety profile, no abuse potential, and it significantly reduces opioid reward in females. Clinical studies examining high-CBD WPE as an adjunct treatment during opioid use disorder are highly warranted.

Involvement of AMPA receptors of lateral habenula in the expression and acquisition phases of morphine-induced place preference

The lateral habenula (LHb), known as the brain structure of the epithalamic, plays the main role in depression and drug addiction. The glutamatergic system influences morphine reward. The effect of activation/inhibition of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors (AMPARs) in the LHb on different phases of morphine-induced conditioned place preference (CPP) remains unknown. In this research, the effect of bilateral intra-LHb microinjection of AMPARs agonist and antagonist on the acquisition and expression phases of CPP in male rats has been investigated. Different doses of NBQX, the antagonist of AMPARs, in combination with the effective dose of morphine, increased the CPP score during the acquisition phase. While AMPA, the agonist of AMPARs, significantly reduced the conditioning scores in the acquisition phase. Pretreatment with NBQX (0.5 and 1 μg/rat) reversed the inhibitory effect of AMPA (1 μg/rat) on the acquisition phase of morphine-induced CPP. The antagonist (1 μg/rat) increased the effect of a high dose of agonist (2 μg/rat) on CPP. On the other hand, NBQX significantly increased CPP scores during the expression phase. AMPA did not significantly affect CPP scores in the expression phase, but significantly reduced locomotor activity in the test phase. These results confirmed the importance of AMPARs in the LHb in morphine reward. Our data also suggest that injection of an AMPARs antagonist into the LHb may alter the AMPA-induced morphine response in a dose-dependent manner.