VF-13, a chimeric peptide of VD-hemopressin(α) and neuropeptide VF, produces potent antinociception with reduced cannabinoid-related side effects

Xu, Biao; Xiao, Jian; Xu, Ke; Zhang, Qinqin; Chen, Dan; Zhang, Run; Zhang, Mengna; Zhu, Huarui; Niu, Jiandong; Zheng, Ting; Li, Ning; Zhang, Xiaoyu; Fang, Quan

doi:10.1016/j.neuropharm.2020.108178

Cited by 6 publications

(17 citation statements)

References 63 publications

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“…The mice were fasted for 16 h with free access to water [ 16 , 47 ]. Drugs were subcutaneously injected 15 min before the oral administration of a charcoal meal (an aqueous suspension of 5% charcoal and 10% gum arable).…”

Section: Methodsmentioning

confidence: 99%

A Novel Multi-Target Mu/Delta Opioid Receptor Agonist, HAGD, Produced Potent Peripheral Antinociception with Limited Side Effects in Mice and Minimal Impact on Human Sperm Motility In Vitro

Feng²,

Zhang³

et al. 2023

Molecules

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Pain is a common clinical symptom among patients. Although various opioid analgesics have been developed, their side effects hinder their application. This study aimed to develop a novel opioid analgesic, HAGD (H-Tyr-D-AIa-GIy-Phe-NH2), with limited side effects. In vivo studies on mouse models as well as in vitro studies on Chinese hamster ovary (CHO) cells expressing human mu, delta, or kappa opioid receptors (CHOhMOP, CHOhDOP, and CHOhKOP, respectively) and human sperm were conducted. Compared with subcutaneous morphine (10 mg/kg), subcutaneous HAGD (10 mg/kg) produced equipotent or even greater antinociception with a prolonged duration by activating mu/delta opioid receptors in preclinical mouse pain models. The analgesic tolerance, rewarding effects (i.e., conditioned place preference and acute hyperlocomotion), and gastrointestinal transit inhibition of HAGD were significantly reduced compared with those of morphine. Both HAGD and morphine exhibited a withdrawal response and had no impacts on motor coordination. In CHOhMOP and CHOhDOP, HAGD showed specific and efficient intracellular Ca2+ stimulation. HAGD had minimal impact on human sperm motility in vitro, whereas 1 × 10−7 and 1 × 10−8 mol/L of morphine significantly declined sperm motility at 3.5 h. Overall, HAGD may serve as a promising antinociceptive compound.

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Section: Methodsmentioning

confidence: 99%

A Novel Multi-Target Mu/Delta Opioid Receptor Agonist, HAGD, Produced Potent Peripheral Antinociception with Limited Side Effects in Mice and Minimal Impact on Human Sperm Motility In Vitro

Feng²,

Zhang³

et al. 2023

Molecules

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“…CHO cells stably expressing CB1 or CB2 receptors were incubated with OCP002 or WIN 5, 212-2 at 37 °C for 10 minutes before being lysed by RIPA lysis. Western blotting was performed as previously reported 17 (Supplemental Digital Content 1, Material, http://links.lww.com/AA/E84). The protein bands were detected using a chemiluminescence system (VILBER) and quantified by Image J.…”

Section: Western Blottingmentioning

confidence: 99%

“…17 Compared with the parent peptide, VD-Hpα-NH 2 produced more potent antinociception and less severe side effects of catalepsy, constipation, and sedation. 17…”

mentioning

confidence: 97%

OCP002, a Mixed Agonist of Opioid and Cannabinoid Receptors, Produces Potent Antinociception With Minimized Side Effects

Zhang

Chen

et al. 2022

Anesthesia &Amp; Analgesia

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BACKGROUND: Increasing attention has been attracted to the development of bifunctional compounds to minimize the side effects of opioid analgesics. Pharmacological studies have verified the functional interaction between opioid and cannabinoid systems in pain management, suggesting that coactivation of the opioid and cannabinoid receptors may provide synergistic analgesia with fewer adverse reactions. Herein, we developed and characterized a novel bifunctional compound containing the pharmacophores of the mu-opioid receptor agonist DALDA and the cannabinoid peptide VD-Hpα-NH2, named OCP002. METHODS: The opioid and cannabinoid agonistic activities of OCP002 were investigated in calcium mobilization and western blotting assays, respectively. Moreover, the central and peripheral antinociceptive effects of OCP002 were evaluated in mouse preclinical models of tail-flick test, carrageenan-induced inflammatory pain, and acetic acid–induced visceral pain, respectively. Furthermore, the potential opioid and cannabinoid side effects of OCP002 were systematically investigated in mice after intracerebroventricular (ICV) and subcutaneous (SC) administrations. RESULTS: OCP002 functioned as a mixed agonist toward mu-opioid, kappa-opioid, and cannabinoid CB1 receptors in vitro. ICV and SC injections of OCP002 produced dose-dependent antinociception in mouse models of nociceptive (the median effective dose [ED50] values with 95% confidence interval [CI] are 0.14 [0.12–0.15] nmol and 0.32 [0.29–0.35] μmol/kg for ICV and SC injections, respectively), inflammatory (mechanical stimulation: ED50 values [95% CI] are 0.76 [0.64–0.90] nmol and 1.23 [1.10–1.38] μmol/kg for ICV and SC injections, respectively; thermal stimulation: ED50 values [95% CI] are 0.13 [0.10–0.17] nmol and 0.23 [0.08–0.40] μmol/kg for ICV and SC injections, respectively), and visceral pain (ED50 values [95% CI] are 0.0069 [0.0050–0.0092] nmol and 1.47 [1.13–1.86] μmol/kg for ICV and SC injections, respectively) via opioid and cannabinoid receptors. Encouragingly, OCP002 cannot cross the blood-brain barrier and exerted nontolerance-forming analgesia over 6-day treatment at both supraspinal and peripheral levels. Consistent with these behavioral results, repeated OCP002 administration did not elicit microglial hypertrophy and proliferation, the typical features of opioid-induced tolerance, in the spinal cord. Furthermore, at the effective analgesic doses, SC OCP002 exhibited minimized opioid and cannabinoid side effects on motor performance, body temperature, gastric motility, physical and psychological dependence, as well as sedation in mice. CONCLUSIONS: This study demonstrates that OCP002 produces potent and nontolerance-forming antinociception in mice with reduced opioid- and cannabinoid-related side effects, which strengthen the candidacy of bifunctional drugs targeting opioid/cannabinoid receptors for translational-medical development to replace or assist the traditional opioid analgesics.

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“…13 For example, a mainly peripherally acting hybrid CB 1 /inducible nitric oxide synthase (iNOS) antagonist is effective in the treatment of experimental liver fibrosis, 161 and the fusion peptide between hemopressin and neuropeptide VF shows potent antinociceptive effects with reduced cannabinoid-related side effects. 162 Comparable approaches have been pursued for interfering with CB 2 receptor activity, although with slower progress. 163 Particularly in the field of neuroinflammation and neurodegeneration, CB 2 receptor agonism seems to be promising.…”

Section: Cannabinoid Receptorsmentioning

confidence: 99%

Neurobiology of cannabinoid receptor signaling

Lutz

2020

Dialogues in Clinical Neuroscience

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The endocannabinoid system (ECS) is a highly versatile signaling system within the nervous system. Despite its widespread localization, its functions within the context of distinct neural processes are very well discernable and specific. This is remarkable, and the question remains as to how such specificity is achieved. One key player in the ECS is the cannabinoid type 1 receptor (CB1), a G protein–coupled receptor characterized by the complexity of its cell-specific expression, cellular and subcellular localization, and its adaptable regulation of intracellular signaling cascades. CB1 receptors are involved in different synaptic and cellular plasticity processes and in the brain’s bioenergetics in a context-specific manner. CB2 receptors are also important in several processes in neurons, glial cells, and immune cells of the brain. As polymorphisms in ECS components, as well as external impacts such as stress and metabolic challenges, can both lead to dysregulated ECS activity and subsequently to possible neuropsychiatric disorders, pharmacological intervention targeting the ECS is a promising therapeutic approach. Understanding the neurobiology of cannabinoid receptor signaling in depth will aid optimal design of therapeutic interventions, minimizing unwanted side effects.

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VF-13, a chimeric peptide of VD-hemopressin(α) and neuropeptide VF, produces potent antinociception with reduced cannabinoid-related side effects

Cited by 6 publications

References 63 publications

A Novel Multi-Target Mu/Delta Opioid Receptor Agonist, HAGD, Produced Potent Peripheral Antinociception with Limited Side Effects in Mice and Minimal Impact on Human Sperm Motility In Vitro

A Novel Multi-Target Mu/Delta Opioid Receptor Agonist, HAGD, Produced Potent Peripheral Antinociception with Limited Side Effects in Mice and Minimal Impact on Human Sperm Motility In Vitro

OCP002, a Mixed Agonist of Opioid and Cannabinoid Receptors, Produces Potent Antinociception With Minimized Side Effects

Neurobiology of cannabinoid receptor signaling

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