The Journal Of Pharmacology And Experimental Therapeutics[JOURNAL]
Sun
200 papers
Chemokine-chemokine receptor networks in conventional type I dendritic cells: an opportunity to prime and boost anticancer immunity.
Kuo N, Shinn CK, Schokrpur S … +3 more , Idoyaga J, Handel T, Gutkind JS
J Pharmacol Exp Ther · 2025 Nov · PMID 41135412 · Full text
Type I conventional dendritic cells (cDC1s) are key drivers of antitumor immunity. In human cancers, their presence correlates with better prognosis and survival benefits. In preclinical mouse tumor models, cDC1s are ind...
Type I conventional dendritic cells (cDC1s) are key drivers of antitumor immunity. In human cancers, their presence correlates with better prognosis and survival benefits. In preclinical mouse tumor models, cDC1s are indispensable for successful T-cell-mediated tumor killing and therapeutic response to immune checkpoint blockade therapies. The essential role of cDC1s in antitumor immunity stems from their ability to uptake tumor-derived antigens and traffic them to the tumor-draining lymph node (tdLN) for T-cell priming. At the tdLN, cDC1s present tumor antigens to naïve CD8 T cells and polarize them into tumor-specific cytotoxic T cells that eventually kill the tumor cells. Within the tumor, cDC1s secrete the chemokines CXCL9 and CXCL10 that recruit CXCR3 effector natural killer and T cells and thereby sustain a local cytotoxic T-cell response. The trafficking and migration of cDC1s to the tumor and tdLNs are largely mediated by a chemokine-chemokine receptor network linking cDC1s to their interacting immune cell partners. In this review, we discuss 2 key chemokine ligand-receptor pairs, C-C chemokine ligand 5-C-C chemokine receptor 5 and X-C chemokine ligand 1-X-C chemokine receptor 1, that play essential roles in directing cDC1 migration to the tumor. Strategies that harness these cDC1-recruiting chemokine systems offer invaluable therapeutic prospects for enhancing current vaccine design and cancer immunotherapies. SIGNIFICANCE STATEMENT: The lack of type I conventional dendritic cells (cDC1s) in tumors represents a major roadblock for current cancer immunotherapies. Here, we highlight 2 chemokines, C-C chemokine ligand 5 and X-C chemokine ligand 1, that are critical for recruiting cDC1s to the tumor microenvironment, where they uptake tumor antigens and cross-present antigens to T cells following migration to the lymph nodes. We further discuss recent advances and limitations in current dendritic cell vaccine design and cancer adjuvant therapies, and propose new strategies to enhance cDC1 recruitment into tumors.
Unraveling synucleinopathies: Recent breakthroughs in Parkinson's disease therapy.
Nanda A, Pandey SK, Singh RK
J Pharmacol Exp Ther · 2025 Nov · PMID 41135411 · Publisher ↗
Parkinson's disease is the most prevalent disorder among a group of conditions known as synucleinopathies. It is characterized by the presence of intracellular inclusions composed of misfolded α-synuclein (α-Syn) protein...
Parkinson's disease is the most prevalent disorder among a group of conditions known as synucleinopathies. It is characterized by the presence of intracellular inclusions composed of misfolded α-synuclein (α-Syn) protein within neurons of the central and peripheral nervous systems. The antibody-based immunotherapeutic approach has substantial promise in treating various types of synucleinopathies, including Parkinson's disease. This review critically examines the pathomechanistic impact of α-Syn on the cellular environment, with a focus on neuroinflammation and immune responses. Various strategies, including active and passive immunization, have been investigated to counteract synucleinopathies. We provide an overview of antibody-based strategies investigated in human clinical trials for the treatment of Parkinson's disease, focusing on cutting-edge approaches, including vaccination therapy, engineered antibody fragments, intrabodies, and nanobodies, designed to combat neuroinflammation-induced neurodegeneration. Harnessing immunotherapy to modulate immune activation has garnered significant interest as a potential therapeutic avenue for various inflammation-linked neurodegenerative disorders. Multiple strategies, including active and passive immunization, have been investigated to target α-Syn. The intricate process of selecting the most effective anti-α-Syn antibody for treating human synucleinopathies requires careful consideration. Additionally, the need for future research and clinical trials must prioritize unlocking the full potential of the immune system to advance our understanding of synucleinopathies. SIGNIFICANCE STATEMENT: This minireview explores recent advances in α-Syn-targeted immunotherapy, antibody fragments, intrabodies, and nanobodies. It highlights their mechanisms and potential to reshape Parkinson's disease treatment through the development of next-generation immunotherapeutics.
The possible protective effect of entacapone on hepatic fibrosis via the fat mass and obesity-associated protein/ N6-methyladenosine/ silent information regulator 1 pathway in a rat model.
Mohamed RH, Kamar SA, Abuamara TMM … +4 more , Tamim YM, Tarek M, Samir N, Magdy YM
J Pharmacol Exp Ther · 2025 Nov · PMID 41129846 · Publisher ↗
The complex molecular pathways behind liver fibrosis (LF) make the existing antifibrotic therapy unsatisfactory. In this work, entacapone's hepatoprotective activity was examined, along with its impact on the hepatic exp...
The complex molecular pathways behind liver fibrosis (LF) make the existing antifibrotic therapy unsatisfactory. In this work, entacapone's hepatoprotective activity was examined, along with its impact on the hepatic expression of fat mass and obesity-associated protein (FTO), N6-methyladenosine (m6A), and silent information regulator (SIRT)1 in a rat model of LF. LF was induced by carbon tetrachloride (CCl) in a dose of 2 mL/kg orally twice weekly throughout the study. Three groups of 30 male Wistar rats were created as follows: (1) control group, (2) LF group, and (3) entacapone-pretreated group. Liver/body weight index and liver function tests were measured. Malondialdehyde, superoxide dismutase, and m6A values, as well as FTO and SIRT1 gene expression, were detected in the liver. Liver histopathology and transforming growth factor β immunohistochemical analysis were assessed. Compared with the LF group, the entacapone-pretreated group showed a decrease in oxidative stress in hepatic tissues and improved hepatic function tests. In comparison with the LF group, this was linked to a decrease in FTO gene expression and an increase in SIRT1 gene expression and the percentage of m6A in total RNA. Additionally, the entacapone-pretreated group decreased the amount of collagen fibers and transforming growth factor β expression, improving the histopathological alterations in the liver. In a rat model of LF, entacapone's hepatoprotective effect may be attributed to the alteration of the FTO/m6A/SIRT1 signaling pathway. The current study may offer entacapone as a promising approach for liver protection during fibrosis. SIGNIFICANCE STATEMENT: The current study suggests that entacapone could increase silent information regulator 1 expression through its effect on fat mass and obesity-associated protein and N6-methyladenosine modulation, providing a promising approach for protecting the liver during fibrosis and identifying a potential new molecular target for the prevention of liver fibrosis.
Sinomenine alleviates cancer-induced bone pain by promoting p65 ubiquitination and modulating microglial polarization.
Sun X, Cao D, Li W … +3 more , Jiang K, Zhu F, Luo D
J Pharmacol Exp Ther · 2025 Nov · PMID 41129845 · Publisher ↗
Cancer-induced bone pain (CIBP), a debilitating complication of metastatic bone cancer, necessitates prompt and effective therapeutic interventions. Sinomenine (SIN), an alkaloid extracted from Sinomenium acutum, demonst...
Cancer-induced bone pain (CIBP), a debilitating complication of metastatic bone cancer, necessitates prompt and effective therapeutic interventions. Sinomenine (SIN), an alkaloid extracted from Sinomenium acutum, demonstrates anti-inflammatory and analgesic properties; nevertheless, its efficacy and mechanisms in CIBP management is inadequately investigated. This study looked at how SIN affected CIBP in a female rat model with bone discomfort caused by tumor implantation and BV2 microglial cells that were activated by lipopolysaccharide (LPS). Behavioral assessments (von Frey filaments and spontaneous activity scoring) showed that SIN administration significantly alleviated mechanical allodynia and ambulatory deficits in CIBP rats. Immunofluorescence assay revealed SIN-mediated suppression of proinflammatory microglial polarization (reduced IBA1/CD86 cells) and promotion of anti-inflammatory phenotypes (increased IBA1/CD206 cells), paralleled by decreased proinflammatory mediators and elevated anti-inflammatory mediators. Mechanistic investigations identified NF-κB p65 activation in both CIBP rats and LPS-treated BV2 cells. SIN induced p65 ubiquitination and proteasomal degradation, as evidenced by cycloheximide/MG132 assays, thereby attenuating NF-κB signaling. Notably, p65 overexpression in CIBP rats reversed SIN's analgesic effects and restored proinflammatory microglial activation, confirming p65's key role in SIN-mediated modulation. These findings collectively demonstrate that SIN alleviates CIBP by partially suppressing NF-κB p65 activity via ubiquitination-dependent degradation, which subsequently inhibits neuroinflammatory microglial polarization. This study positions SIN as a promising candidate for managing cancer-related bone pain. SIGNIFICANCE STATEMENT: Sinomenine (SIN) is a novel inhibitor of cancer-induced bone pain (CIBP). SIN suppressed the nuclear factor κB inflammatory pathway and reduced M1 polarization in microglial functional assays. In a rat CIBP model, SIN effectively alleviated mechanical allodynia and motor dysfunction, while downregulating nuclear factor κB activation and proinflammatory factor expression. These findings suggest SIN's dual therapeutic potential for simultaneous analgesia and anti-inflammatory effects in CIBP management.
Effects of δ opioid receptor stimulation via SNC80 on conditioned reinforcing properties of a remifentanil-associated stimulus.
Robertson SH, Burgess GE, Jutkiewicz EM … +1 more , Rice KC
J Pharmacol Exp Ther · 2025 Nov · PMID 41129844 · Full text
Substance use disorder is associated with a high rate of relapse driven by the rewarding and motivational properties of drug-associated stimuli. We examined the extent to which the δ opioid receptor (DOR) mediated the co...
Substance use disorder is associated with a high rate of relapse driven by the rewarding and motivational properties of drug-associated stimuli. We examined the extent to which the δ opioid receptor (DOR) mediated the conditioned reinforcing properties of drug-associated stimuli across 4 experiments and 2 operant procedures in Sprague-Dawley rats. In experiment 1, we assessed the extent to which SNC80 (DOR agonist) altered responding during extinction in a remifentanil self-administration procedure. In experiment 2, we assessed the extent to which SNC80 altered responding for a remifentanil-associated stimulus in the new response acquisition procedure. In experiment 3, we assessed the extent to which the effects of SNC80 were altered in standard versus enhanced stimulus control conditions in the new response acquisition procedure. In experiment 4, we assessed the extent to which naltrindole (DOR antagonist) was able to block SNC80-induced alterations in responding for a remifentanil-associated stimulus in the new response acquisition procedure. In experiment 5, we assessed the extent to which pretreatments of SNC80 altered Pavlovian conditioning in the new response acquisition procedure. These experiments support the role of the DOR system in mediating the rewarding properties of drug-associated stimuli, such that SNC80 dose-dependently enhanced responding for a remifentanil-associated stimulus across self-administration and new response acquisition procedures. These effects were blocked by naltrindole, demonstrating that these are DOR-mediated effects. DORs may represent a promising target to address relapse. SIGNIFICANCE STATEMENT: Conditioned reinforcing effects of an opioid-associated cue were enhanced following stimulation of δ opioid receptors (DORs), and this effect was blocked via DOR antagonism, which suggests the role of DORs in mediating drug-associated conditioned reinforcement.
Pharmacological and toxicological profiling of JAMC-4/108: targeted induction of apoptosis in human colorectal cancer cells.
Paduch R, Mizerska-Kowalska M, Dudzińska E … +6 more , Koszła O, Kukula-Koch W, Tabęcka-Łonczyńska A, Batjargal A, Nowak R, Sołek P
J Pharmacol Exp Ther · 2025 Nov · PMID 41124967 · Publisher ↗
Colorectal cancer remains a leading cause of cancer-related mortality, necessitating the development of novel therapeutic strategies. In this study, we investigate the pharmacological and toxicological properties of JAMC...
Colorectal cancer remains a leading cause of cancer-related mortality, necessitating the development of novel therapeutic strategies. In this study, we investigate the pharmacological and toxicological properties of JAMC-4/108, a traditional Mongolian herbal extract, in human colonic adenocarcinoma (HT-29) and normal colonic epithelial (CCD 841 CoTr) cells. Using high-performance liquid chromatography-electrospray ionization-quadrupole time-of-flight-tandem mass spectrometry fingerprinting, we characterized its chemical composition, while a combination of cellular, biochemical and molecular assays provided mechanistic insights into its cytotoxic effects. The ethanol extract of JAMC-4/108 exhibited substantial selective cytotoxicity in HT-29 cells by inducing apoptosis and necrosis via caspase-3, cleaved caspase-7 and poly(ADP-ribose) polymerase activation, while the water extract primarily triggered caspase-9-mediated apoptosis. Both extracts modulated oxidative stress pathways, increasing Nrf2, Keap1 and LC3A/B levels, with the ethanol extract also upregulating NQO1, suggesting metabolic implications. In contrast, the ethanol extract had minimal apoptotic effects in normal colonic epithelial cells, whereas the water extract primarily influenced caspase-9 expression, indicating a distinct toxicity profile. Additionally, both extracts altered cell cycle progression-stimulated NOx release and modulated Fe ion and DPPH radical pools in a concentration-dependent manner. Our findings highlight the selective anticancer potential of JAMC-4/108 and provide mechanistic insights into its pharmacological and toxicological effects, supporting its further evaluation for therapeutic development and safety assessment. SIGNIFICANCE STATEMENT: This study demonstrates the selective anticancer activity of JAMC-4/108, a Mongolian herbal extract, against colorectal cancer cells, with distinct apoptotic mechanisms and minimal toxicity to normal cells. These findings support the potential of JAMC-4/108 as a novel therapeutic candidate for colorectal cancer treatment, highlighting its pharmacological efficacy and safety profile for further development.
Development of CAL101-a humanized monoclonal antibody targeting S100A4 to inhibit proinflammatory and profibrotic signaling.
Borchert SV, Hallén J, Hussain RI … +3 more , Holyer I, Troelsen JT, Klingelhöfer J
J Pharmacol Exp Ther · 2025 Nov · PMID 41124966 · Publisher ↗
S100A4, a member of the S100 family of calcium-binding proteins, acts as a damage-associated molecular pattern with a central role in modulating inflammatory and fibrotic responses. Upon extracellular release, S100A4 eng...
S100A4, a member of the S100 family of calcium-binding proteins, acts as a damage-associated molecular pattern with a central role in modulating inflammatory and fibrotic responses. Upon extracellular release, S100A4 engages receptors such as toll-like receptor 4, triggering signaling cascades that amplify proinflammatory cytokine production and promote fibrotic tissue remodeling, positioning it as a promising therapeutic target. This study describes the development and characterization of CAL101, a humanized IgG4 monoclonal antibody, which binds with high affinity to the S100A4 target-binding interface. CAL101 exhibits strong cross-species reactivity, effectively binding S100A4 from human, cynomolgus monkey, mouse, and rat. Functional assays demonstrate that CAL101 inhibits toll-like receptor 4 and transforming growth factor β pathway activation in reporter cell lines and decreases cytokine release in human monocytes and whole blood cell cultures. These findings support continued development of CAL101 as a therapeutic candidate for fibrotic and chronic inflammatory diseases. A recently completed phase I trial (ClinicalTrials.gov ID NCT05965089) established the safety, pharmacokinetic, and immunogenicity profile of CAL101. A phase II trial in patients with idiopathic pulmonary fibrosis has been initiated (ClinicalTrials.gov ID NCT06736990). SIGNIFICANT STATEMENT: This article presents the development and characterization of CAL101, a first-in-class humanized IgG4 antibody that neutralizes S100A4 by blocking its receptor interactions. CAL101 suppresses inflammatory and fibrotic signaling and is currently in phase II trial for idiopathic pulmonary fibrosis.
Oxycodone self-administration and drug-primed responding in male and female squirrel monkeys: Effects of alternative reinforcer availability.
de Moura FB, Booth RG, Kohut SJ
J Pharmacol Exp Ther · 2025 Nov · PMID 41110332 · Publisher ↗
Nondrug alternative reinforcers have long been used as a component of therapeutic interventions for the management of substance use disorder; however, the conditions under which alternative reinforcers are most effective...
Nondrug alternative reinforcers have long been used as a component of therapeutic interventions for the management of substance use disorder; however, the conditions under which alternative reinforcers are most effective are not well characterized. This study evaluated the impact of varying the magnitude of an alternative reinforcer on oxycodone self-administration and drug-primed responding in male and female squirrel monkeys. Subjects (n = 4/sex) were trained under concurrent second-order schedules of reinforcement for intravenous oxycodone (0.001-0.1 mg/kg per injection) on one lever and sweetened condensed milk (5%, 10%, 20%, and 30% in water) on another. Oxycodone-primed responding was evaluated by administering 0.32 mg/kg of oxycodone prior to sessions in which saline was available on the drug-paired lever. During oxycodone self-administration sessions, milk availability decreased oxycodone self-administration and preference in a concentration-dependent manner; low milk concentrations were more effective at decreasing oxycodone's reinforcing potency in males. During priming tests, milk significantly attenuated oxycodone-primed responding in both males and females; low milk concentrations were more effective at decreasing the priming effects of oxycodone in females. That alternative reinforcers differentially impacted self-administration and oxycodone-primed responding in a sex-dependent manner suggests that treatment strategies that use alternative reinforcers may be more effective in males or females depending on when they are implemented. SIGNIFICANCE STATEMENT: The use of nondrug reinforcer alternatives is a key component of many therapeutic interventions for substance use disorder. However, the variables that influence response to alternative reinforcers remain incompletely understood. This study investigated how varying the magnitude of an alternative reinforcer impacts oxycodone self-administration and drug-primed responding in male and female squirrel monkeys. Overall, the findings indicate that alternative reinforcers affect self-administration and oxycodone-primed responding differently depending on sex.
Targeting the gate: The rise of Sec61 inhibitors in cancer therapy.
Tadesse S, Kaweesa E
J Pharmacol Exp Ther · 2025 Nov · PMID 41110331 · Publisher ↗
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Beyond muscle: Exploring NAD for neurovascular and cognitive preservation in older patients with peripheral artery disease.
Zhou Y, Wu CY, Lee RH
J Pharmacol Exp Ther · 2025 Nov · PMID 41110330 · Full text
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Inhibition of cyclin-dependent kinase 4/6 attenuates airway remodeling in a murine severe asthma model by suppressing group 2 innate lymphoid cells proliferation.
Matsuda M, Ishizu E, Fujiwara Y … +5 more , Shimora H, Kaibori Y, Yamagishi N, Kaminuma O, Nabe T
J Pharmacol Exp Ther · 2025 Nov · PMID 41109069 · Publisher ↗
Severe asthma is characterized by persistent airway inflammation and structural remodeling, including mucus accumulation, epithelial thickening, and subepithelial fibrosis, which are often refractory to conventional ther...
Severe asthma is characterized by persistent airway inflammation and structural remodeling, including mucus accumulation, epithelial thickening, and subepithelial fibrosis, which are often refractory to conventional therapies. Group 2 innate lymphoid cells (ILC2s) contribute to these pathological changes by producing large amounts of interleukin-5, interleukin-13, and amphiregulin. Although cell cycle regulators have been implicated in immune cell proliferation, their role in ILC2-driven asthma pathogenesis remains unexplored. Here, we identified the cyclin-dependent kinase (CDK) 4/6-ILC2 axis as a previously unrecognized driver of airway remodeling in severe asthma. Using an ovalbumin (OVA)-induced mouse model of severe asthma, we demonstrated that (1) CDK4 and CDK6 cells were elevated by 4.0- and 4.5-fold, respectively, in the lungs; (2) treatment with the CDK4/6 inhibitor palbociclib reduced fibrosis and ILC2 expansion by 77% and 87%, respectively; (3) increased ILC2s in the lungs showed high gene expression levels of CDK4, CDK6, and profibrotic factors, including fibroblast growth factor 2, fibroblast growth factor 23, collagen (COL) 4A2, COL10A1, and COL18A1; (4) thymic stromal lymphopoietin stimulation enhanced CDK4/6 protein expression in ILC2s, leading to their proliferation; and (5) palbociclib significantly inhibited the proliferation of ILC2s, at least in part by suppressing retinoblastoma phosphorylation. These findings establish CDK4/6 as a novel molecular pathway regulating ILC2-mediated airway remodeling and highlight its inhibition as a promising therapeutic approach for severe asthma. SIGNIFICANCE STATEMENT: Although cell cycle regulators have been implicated in immune cell proliferation, their role in group 2 innate lymphoid cell-driven asthma pathogenesis remains unexplored. Here, we identified the cyclin-dependent kinase 4/6-group 2 innate lymphoid cell axis as a previously unrecognized driver of airway remodeling in severe asthma.
Phosphatidylinositol 3-kinase and mechanistic target of rapamycin dualinhibitor, VDC597, as a therapeutic agent for canine osteosarcoma.
Meuten T, Farrell KB, Rose BJ … +4 more , Brill SA, Brady RV, Schlein LJ, Thamm DH
J Pharmacol Exp Ther · 2025 Oct · PMID 41106249 · Full text
Canine osteosarcoma (OS) presents a significant clinical challenge in veterinary oncology. Due to the similarities in aggressive biologic behavior, mutation status, and gene expression profiles, the canine patient also p...
Canine osteosarcoma (OS) presents a significant clinical challenge in veterinary oncology. Due to the similarities in aggressive biologic behavior, mutation status, and gene expression profiles, the canine patient also provides a spontaneous animal model for OS in humans. Advancements in the treatment of OS have been slow to progress. The phosphatidylinositol 3-kinase (PI3K), AKT serine/threonine kinase (AKT), and mechanistic target of rapamycin (mTOR) signal transduction pathway is implicated in canine and human OS, and presents a potentially valuable therapeutic target. The present study investigated PI3K-AKT-mTOR signaling activity in canine OS cells and the in vitro and in vivo efficacy of a PI3K/mTOR dual inhibitor alone and in combination with cytotoxic chemotherapy drugs for treatment of canine OS. The results of this study demonstrate reduced signal transduction; increased cell death; reduced cell proliferation, migration, invasion, and vascular endothelial growth factor production in vitro; as well as reduced tumor growth and greater survival times with inhibition of PI3K-AKT-mTOR signaling in a xenograft mouse model. We also examined patient-derived tumors for immunoreactivity of forkhead box O1, a downstream target of AKT activation. Unlike the xenograft tumors that were treated with a PI3K/mTOR inhibitor, a correlation between tumor biologic behavior and forkhead box O1 immunoreactivity was not present in the patient-derived tumor sections. These findings indicate both the potential benefits of PI3K/mTOR dual inhibitors in chemotherapeutic protocols and the need for further study of patient-derived tumors to better understand the extent of PI3K-AKT-mTOR activation for the application of such targeted inhibitors. SIGNIFICANCE STATEMENT: The phosphatidylinositol 3-kinase, AKT serine/threonine kinase, and mechanistic target of rapamycin pathway is frequently dysregulated in canine osteosarcoma. VDC597, a dual inhibitor of pathway activation, can potentially improve outcomes of canine osteosarcoma. In vitro, VDC597 inhibited cellular viability, migration, and invasion, vascular endothelial growth factor production, and phosphorylation of signaling proteins, while promoting cell death. In mice treated with VDC597, tumor growth slowed and survival times increased. Effects were found both with VDC597 alone and in combination with other chemotherapy drugs.
Mitragynine and 7-hydroxymitragynine: Bidirectional effects on breathing in rats.
Zuarth Gonzalez JD, Ragsdale AK, Mukhopadhyay S … +4 more , McCurdy CR, McMahon LR, Obeng S, Wilkerson JL
J Pharmacol Exp Ther · 2025 Nov · PMID 41106041 · Full text
The use of kratom as an alternative to conventional opioids has surged, driven largely by anecdotal reports of its efficacy for pain relief and opioid withdrawal management. The growing prevalence of kratom products enri...
The use of kratom as an alternative to conventional opioids has surged, driven largely by anecdotal reports of its efficacy for pain relief and opioid withdrawal management. The growing prevalence of kratom products enriched with 7-hydroxymitragynine (7-HMG), an active metabolite of mitragynine (MG), necessitates evaluating the respiratory effects of these alkaloids and determining whether naloxone reverses their potential respiratory depressant effects. Respiratory parameters were measured in awake, freely moving female and male Sprague-Dawley rats using whole body plethysmography. To minimize handling-induced artifacts and ensure precise respiratory recordings, drugs were administered intravenously. Morphine and 7-HMG induced significant respiratory depression, evidenced by reductions in breathing frequency, tidal volume, and minute volume. The potency of 7-HMG to decrease minute volume by 50% was 4.5-fold greater than that of morphine. In contrast, MG administration unexpectedly increased respiratory frequency. Naloxone fully reversed the respiratory depression induced by both morphine and 7-HMG but did not alter the respiratory stimulant effects produced by MG. These findings demonstrate that 7-HMG exhibits significant respiratory depressant properties similar to classical opioids, and importantly, such depressant effects are effectively antagonized by naloxone. Conversely, MG exerts respiratory stimulant effects through mechanisms independent of opioid receptor pathways. Collectively, these data highlight crucial pharmacological distinctions between kratom alkaloids, underscoring the risk associated with high 7-HMG-containing kratom products and suggesting that the predominant alkaloid MG may offer a safer respiratory profile. SIGNIFICANCE STATEMENT: The prevalence of kratom products containing 7-hydroxymitragynine (7-HMG), a μ-opioid receptor agonist, underscores the need to evaluate respiratory effects of kratom-related alkaloids and their reversal by naloxone. 7-HMG induced significant respiratory depression comparable with morphine, which was reversed by naloxone. Conversely, mitragynine, kratom's most abundant alkaloid, unexpectedly increased respiratory frequency unaffected by naloxone. These findings highlight critical pharmacological differences between kratom-related alkaloids, emphasizing potential risks associated with products containing high concentrations of 7-HMG.
Dose-dependent, opioid-induced sleep disruption is partially mediated by motor activity but not by body temperature in C57BL/6J mice.
Unzaga DZ, O'Brien CB, Cooper NW … +6 more , Olson CE, Zhu X, O'Neil MA, Price JM, Lydic R, Baghdoyan HA
J Pharmacol Exp Ther · 2025 Oct · PMID 41101187 · Publisher ↗
States of sleep and wakefulness, motor activity, and body temperature are temporally linked, yet these variables are often studied independently. Here, we report novel results from male C57BL/6J mice (n = 24) that quanti...
States of sleep and wakefulness, motor activity, and body temperature are temporally linked, yet these variables are often studied independently. Here, we report novel results from male C57BL/6J mice (n = 24) that quantify the causal and correlational relationships between these temporally linked measures. The initial experiments used 12 mice to identify the lowest antinociceptive doses of fentanyl (0.1 mg/kg) and morphine (1 mg/kg). Twelve additional mice were implanted with telemeters to simultaneously record electroencephalogram, electromyogram, motor activity, and subcutaneous body temperature. Doses of fentanyl (0.1, 0.3, 1, 3 mg/kg) and morphine (1, 3, 10, 30 mg/kg) caused significant (P < .05) increases in wakefulness and decreases in non-rapid eye movement and rapid eye movement sleep. Fentanyl (0.1-3 mg/kg) and morphine (3-30 mg/kg) significantly increased motor activity. Body temperature during wakefulness was significantly decreased by fentanyl (1 and 3 mg/kg). Morphine increased (3 mg/kg) and decreased (30 mg/kg) body temperature. Mediation analyses showed that the increase in wakefulness caused by fentanyl and morphine was partially mediated by motor activity but not by changes in body temperature. These results provide the first complete dose-response data for the effects of fentanyl and morphine on simultaneously acquired measures of sleep/wake states, body temperature, and motor activity. Compared with human data, these results from mice reveal similarities (sleep disruption, hyperthermia and hypothermia, muscle rigidity) and differences (increased motor activity) caused by fentanyl and morphine. The results also demonstrate the power of mediation analyses for providing nuanced insights into opioid effects on clinically relevant neurobehavioral phenotypes. SIGNIFICANCE STATEMENT: This study demonstrated that in mice, even the lowest doses of fentanyl and morphine that caused antinociception also caused sleep disruption. Thus, in mice, it is not possible to provide antinociception using fentanyl or morphine without causing sleep disruption.
Dual sigma receptor/dopamine transporter inhibition and the union of pharmacology and experimental psychology.
Katz JL
J Pharmacol Exp Ther · 2025 Oct · PMID 41092850 · Full text
Selective standard sigma receptor (σR) antagonists block several behavioral effects of cocaine though they are inactive in altering cocaine self-administration. However, σR antagonists with affinity for the dopamine tran...
Selective standard sigma receptor (σR) antagonists block several behavioral effects of cocaine though they are inactive in altering cocaine self-administration. However, σR antagonists with affinity for the dopamine transporter (DAT) were effective in decreasing maximal cocaine self-administration. Additionally, σR/DAT inhibition affected cocaine or methamphetamine self-administration at doses that had minimal effects on comparable responding maintained by food reinforcement, suggesting that σR/DAT inhibition may serve as a lead for the discovery of stimulant-abuse medications. Further, molecular interactions of σRs and the DAT provide several leads for understanding the mechanisms that may underlie this unique behavioral effect. Despite decreasing stimulant self-administration, dual σR/DAT inhibition only enhanced the discriminative-stimulus effects of cocaine. This outcome would be considered paradoxical if self-administration is based on subjective effects identical to those on which the discrimination is based. Resolving this conundrum of outcomes under 2 procedures, both thought to relate to abuse liability, is suggested by a behavioral analysis of how the drugs function under the 2 procedures. In self-administration procedures, cocaine functions as a reinforcing consequence, whereas in discrimination procedures, cocaine functions as an antecedent stimulus that sets the occasion for responses. Although the subjective nature of that antecedent stimulus is unknown, it is proposed that it contains elements of the experience accompanying cocaine-induced satiety. Evidence supporting σR/DAT inhibition producing an effect related to cocaine-induced satiety is supported by the behavioral economics of cocaine self-administration. Importantly, the potential resolution of this paradox comes from conceptualizing behavioral pharmacology as a union of pharmacology and behavior analysis. SIGNIFICANCE STATEMENT: Sigma receptor (σR) antagonist actions combined with dopamine transport (DAT) inhibition decreased cocaine self-administration, suggesting avenues for stimulant-abuse medications discovery. However, σR/DAT inhibition enhanced the discriminative-stimulus effects of cocaine, an ostensible paradox. Resolving the enigma, it is proposed that the experience of σR/DAT inhibition contains subjective elements of cocaine-induced satiety, and supporting evidence, including the behavioral economics of cocaine self-administration, is outlined. Importantly, the resolution of this paradox comes from conceptualizing behavioral pharmacology as a union of pharmacology and experimental psychology.
Fixed-proportion mixtures with the α2-adrenergic agonist clonidine or lofexidine do not alter fentanyl self-administration in non-opioid-dependent male and female rats.
Ortiz A, St Onge CM, Banks ML
J Pharmacol Exp Ther · 2025 Oct · PMID 41075537 · Full text
Illicitly manufactured fentanyl has increasingly been adulterated with other chemical substances such as α2-adrenergic agonists. Although xylazine was the initial α-2 agonist reported to be in the illicit fentanyl supply...
Illicitly manufactured fentanyl has increasingly been adulterated with other chemical substances such as α2-adrenergic agonists. Although xylazine was the initial α-2 agonist reported to be in the illicit fentanyl supply, other α-2 agonists are increasingly being identified, suggesting that xylazine adulteration of illicit fentanyl is intentional to augment fentanyl effects. The aim of the present study was to determine the interactions between 2 clinically available α-2 agonists, clonidine and lofexidine, and fentanyl on reinforcement endpoints in male and female rats. Three drug self-administration experiments were conducted. First, clonidine and lofexidine self-administration dose-effect functions were determined under a fixed-ratio 5 schedule to assess whether clonidine or lofexidine functioned as reinforcers in rats. Second, behavioral economic demand functions were determined for fentanyl alone, α-2 agonists alone, or several fixed-proportion fentanyl/α-2 agonist mixtures. Lastly, fentanyl/α-2 agonist interactions were determined under a concurrent schedule of fixed-proportion fentanyl/α-2 agonist mixture and food availability. Neither clonidine nor lofexidine functioned as reinforcers under the fixed-ratio 5 schedule, even at the largest doses examined, which produced behavioral sedation. The present results demonstrate that clonidine and other α-2 agonists do not function as reinforcers under limited-access conditions in nonopioid-dependent rats. Furthermore, fentanyl self-administration was not significantly altered by increasing fixed-proportion mixtures of clonidine or lofexidine under either behavioral economic demand or fentanyl versus food choice procedures. Overall, these results demonstrate that α-2 agonists do not modulate fentanyl reinforcement in nonopioid-dependent rats and suggest that other potential reasons need to be explored for α-2 agonist adulteration of illicitly manufactured fentanyl. SIGNIFICANCE STATEMENT: Illicitly manufactured fentanyl continues to be adulterated with α-2 agonists. The present results demonstrate that clonidine and lofexidine neither enhance nor attenuate fentanyl self-administration under either behavioral economic demand or drug-choice procedures. These results suggest other factors than reinforcement modulation should be examined regarding the premise for α-2 agonist adulteration of illicitly manufactured fentanyl.
Nonpharmacological and pharmacological influences on opioid effects: A review of clinical research findings.
Luba R, Comer SD
J Pharmacol Exp Ther · 2025 Oct · PMID 41075536 · Full text
The current opioid crisis underscores the need for continued research on variables that affect opioid self-administration and strategies to alter this behavior. Decades of human behavioral pharmacology studies suggest th...
The current opioid crisis underscores the need for continued research on variables that affect opioid self-administration and strategies to alter this behavior. Decades of human behavioral pharmacology studies suggest that a range of nonpharmacological and pharmacological factors influence the effects of opioids. This review focuses on consolidating findings on the influence of experimental conditions on opioid effects, with a particular emphasis on subjective effects and reinforcement. We describe different schedules of reinforcement that have been used in studies of opioid self-administration in humans, and we review the influence of pain, stress, and individual characteristics (eg, sex, genetic factors, and psychiatric comorbidity) on opioid effects. Some pharmacological variables (eg, routes and rates of drug administration, dosing intervals, and state of physical dependence) also are reviewed to highlight the profound influence these variables can have on the subjective and reinforcing effects of opioids. We conclude with commentary on current gaps in and challenges to characterizing opioid effects in behavioral pharmacology experiments and future directions for this area of scientific inquiry. SIGNIFICANCE STATEMENT: This review highlights and summarizes findings on nonpharmacological and pharmacological influences on opioid effects, synthesized from the last several decades of clinical studies. This review focuses on behavioral pharmacology studies that explore the subjective and reinforcing effects of opioids and human research examining individual characteristics that influence opioid effects.
Secondary analyses of the effects of nicotine dose and dose expectancy on puff- and segment-level smoking topography.
Pierce-Messick ZJ, Bergeria CL, Lee DC … +2 more , Kumar L, Strickland JC
J Pharmacol Exp Ther · 2025 Oct · PMID 41072131 · Publisher ↗
Puff topography (patterns of puffing behavior) is often measured in tobacco regulatory science. However, analyses typically focus on overall mean puff topography outcomes and not on in-depth analysis of patterns of behav...
Puff topography (patterns of puffing behavior) is often measured in tobacco regulatory science. However, analyses typically focus on overall mean puff topography outcomes and not on in-depth analysis of patterns of behavior. In this secondary analysis, we evaluated puff-level and segment-level metrics that may prove useful in the analysis of smoking behavior with promising applications to clinical research and tobacco cessation outcomes. People with daily cigarette use (N = 21; 9 female) completed 4 experimental sessions in which nicotine dose expectancy and nicotine dose (0.80 mg vs 0.03 mg yield) were manipulated. Participants smoked a cigarette in the laboratory during a 10-minute sampling period and puff topography data were collected. Topography was investigated using puff-level measures (eg, time-to-volume metrics) in addition to a segment-level analysis that separated smoking segments by 5-, 10-, and 30-second intervals. Analyses evaluated main and interactive effects of expectancy and nicotine dose on overall puff topography as well as segment outcomes. Analyses demonstrated that low-dose nicotine, but not low-dose expectancy, resulted in a reduced number of smoking segments (P = .006), increased puffs per segment (P = .013), and more rapid time-to-volume metrics (eg, time-to-half total volume) (P < .005). Dose-related differences remained when controlling for traditional measures (eg, average puff duration) suggesting unique utility of these analyses. These data document the use of puff- and segment-level analyses in evaluating pharmacological and contextual moderators of smoking behavior as well as the flexibility of within-session topography data for alternative behavioral analyses. SIGNIFICANCE STATEMENT: Participants smoked low-nicotine dose cigarettes more quickly than full-nicotine cigarettes but showed no other differences in overall puff topography. An approach to analyzing topography by creating smoking activity segments defined by different interpuff intervals suggested altered smoking dynamics dependent on dose, such as fewer overall segments with low-nicotine cigarettes. This approach has potential utility and can be readily applied to existing puff topography data.
Exercise is required to maintain unacylated ghrelin response in adult male rat skeletal muscle, regardless of dietary fat consumption.
Notaro NM, Budd JM, Green LA … +2 more , Caruso BR, Dyck DJ
J Pharmacol Exp Ther · 2025 Oct · PMID 41067117 · Full text
Unacylated ghrelin (unAG) stimulates fatty acid oxidation (FAO) in isolated male rat skeletal muscle. However, 6 weeks of high-fat feeding results in "ghrelin resistance," or loss of this effect. Recent work has indicate...
Unacylated ghrelin (unAG) stimulates fatty acid oxidation (FAO) in isolated male rat skeletal muscle. However, 6 weeks of high-fat feeding results in "ghrelin resistance," or loss of this effect. Recent work has indicated that sedentary behavior may be a main contributor to the loss of skeletal muscle unAG response, potentially representing an early disruption in lipid metabolism in the development of metabolic disease. Therefore, the objective of this study was to investigate whether exercise is required to maintain the stimulatory effect of unAG on FAO in skeletal muscle and if the exercise intensity needed is dependent on dietary fat intake. Male rats were fed either a low- or high-fat diet for 6 weeks while remaining sedentary, or performing low- or high-intensity exercise. Soleus muscle strips were isolated and assessed for their ability to respond to unAG by increasing FAO. High-intensity exercise preserved unAG response under both low-fat and high-fat dietary conditions, an effect not observed in sedentary or low-exercise groups. Additional soleus muscle strips were collected from all groups to assess the activation of the AMP-activated protein kinase-acetyl-CoA carboxylase axis and Ca2+ signaling in response to unAG; however, these pathways were not found to be significantly activated. Exercise also increased corticotropin-releasing factor 2 receptor content, the putative receptor through which unAG signals in skeletal muscle, whereas high-fat feeding had an overall effect to reduce it. However, unAG treatment did not activate cAMP/protein kinase A signaling. These findings demonstrate a protective role of exercise in maintaining skeletal muscle unAG response, although mechanisms remain to be fully elucidated. SIGNIFICANCE STATEMENT: Unacylated ghrelin stimulates fatty acid oxidation and protects insulin response in skeletal muscle; this response is lost with physical inactivity. We demonstrate that high-intensity exercise preserves this response, potentially due to changes in corticotropin-releasing factor 2 receptor content.
Corrigendum to "Acetylcholinesterase Inhibitors for Alzheimer's Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation" [The Journal of Pharmacology and Experimental Therapeutics 359 (2016) 374-382].
Zhang J, Zhang L, Sun X … +7 more , Yang Y, Kong L, Lu C, Lv G, Wang T, Wang H, Fu F
J Pharmacol Exp Ther · 2025 Oct · PMID 41061323 · Publisher ↗
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