Opioid use disorder (OUD) has become a considerable global public health challenge; however, potential medications for the management of OUD that are effective, safe, and nonaddictive are not available. Accumulating preclinical evidence indicates that antagonists of the dopamine D₃ receptor (D₃R) have effects on addiction in different animal models. We have previously reported that YQA14, a D₃R antagonist, exhibits very high affinity and selectivity for D₃Rs over D₂Rs, and is able to inhibit cocaine- or methamphetamine-induced reinforcement and reinstatement in self-administration tests. In the present study, our results illustrated that YQA14 dose-dependently reduced infusions under the fixed-ratio 2 procedure and lowered the breakpoint under the progressive-ratio procedure in heroin self-administered rats, also attenuated heroin-induced reinstatement of drug-seeking behavior. On the other hand, YQA14 not only reduced morphine-induced expression of conditioned place preference but also facilitated the extinguishing process in mice. Moreover, we elucidated that YQA14 attenuated opioid-induced reward or reinforcement mainly by inhibiting morphine-induced up-regulation of dopaminergic neuron activity in the ventral tegmental area and decreasing dopamine release in the nucleus accumbens with a fiber photometry recording system. These findings suggest that D₃R might play a very important role in opioid addiction, and YQA14 may have pharmacotherapeutic potential in attenuating opioid-induced addictive behaviors dependent on the dopamine system.
Rats ; Mice ; Animals ; Analgesics, Opioid ; Dopamine ; Heroin/pharmacology* ; Dopamine Antagonists/pharmacology* ; Receptors, Dopamine D3/metabolism* ; Morphine/pharmacology* ; Behavior, Addictive/drug therapy* ; Self Administration

Humans ; Dynorphins/metabolism* ; Receptors, Opioid, kappa/metabolism* ; Cryoelectron Microscopy

Spinal cord stimulation (SCS)-induced analgesia was characterized, and its underlying mechanisms were examined in a spared nerve injury model of neuropathic pain in rats. The analgesic effect of SCS with moderate mechanical hypersensitivity was increased with increasing stimulation intensity between the 20% and 80% motor thresholds. Various frequencies (2, 15, 50, 100, 10000 Hz, and 2/100 Hz dense-dispersed) of SCS were similarly effective. SCS-induced analgesia was maintained without tolerance within 24 h of continuous stimulation. SCS at 2 Hz significantly increased methionine enkephalin content in the cerebrospinal fluid. The analgesic effect of 2 Hz was abolished by μ or κ opioid receptor antagonist. The effect of 100 Hz was prevented by a κ antagonist, and that of 10 kHz was blocked by any of the μ, δ, or κ receptor antagonists, suggesting that the analgesic effect of SCS at different frequencies is mediated by different endorphins and opioid receptors.
Analgesics ; Animals ; Narcotic Antagonists/pharmacology* ; Neuralgia/therapy* ; Opioid Peptides ; Rats ; Receptors, Opioid/physiology* ; Receptors, Opioid, kappa ; Spinal Cord ; Spinal Cord Stimulation

Objective: To explore the effects of the mu-opioid receptor (MOR) in the paraventricular nucleus (PVN) on the ejaculatory behaviors of male rats and its potential mechanisms. METHODS: Male SD rats with normal ejaculation ability were mated with female ones in hormone-induced estrus. After bilateral PVN microinjection of D-Ala-2-Me-Phe-4-Gly-ol enkephalin (DAGO) or D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP) with an inserted catheter, the male animals were observed for mount latency (ML), mount frequency (MF), intromission latency (IL), intromission frequency (IF), ejaculation latency (EL), ejaculation frequency (EF), post-ejaculation interval (PEI), and intromission ratio (IR). The lumbar sympathetic nerve activity (LSNA) of the rats was recorded using the PowerLab data acquisition hardware device, and the levels of norepinephrine (NE) in the peripheral plasma were measured by ELISA following microinjection of saline or different doses of DAGO or CTAP. RESULTS: Neither CTAP nor DGAO significantly affected the ML of the male rats (P > 0.05). DGAO remarkably increased IF (P < 0.01) and MF (P < 0.01), prolonged IL (P < 0.01), EL (P < 0.01) and PEI (P < 0.01), and reduced EF (P <0.01) and IR (P < 0.05). On the contrary, CTAP markedly decreased IF (P < 0.01) and MF (P < 0.01), shortened IL (P < 0.01), EL (P < 0.01) and PFI (P < 0.01), and elevated EF (P < 0.01) and IR (P < 0.01). Additionally, DAGO decreased LSNA in a dose-dependent manner and reduced the NE level in the peripheral plasma. CTAP, however, not only offset the effects of DAGO on LSNA, but also significantly increased LSNA. CONCLUSIONS MOR in PVN inhibits ejaculatory behaviors in male rats by weakening LSNA, which has provided some theoretical evidence for the use of highly selective opioids in the treatment of premature ejaculation.
Animals ; Ejaculation ; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-/pharmacology* ; Female ; Male ; Paraventricular Hypothalamic Nucleus/physiology* ; Peptide Fragments/pharmacology* ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, mu/physiology* ; Somatostatin/pharmacology* ; Sympathetic Nervous System/physiology*

OBJECTIVE: To observe the effect of early intervention of bone-nearby acupuncture (BNA) combined with electroacupuncture (EA) on the expression of histone deacetylase1(HDAC1), histone deacetylase 2 (HDAC2) andμ-opioid recepter (MOR) in dorsal root ganglia (DRG) of bone cancer pain-morphine tolerance (BCP-MT) rats, and to explore its possible mechanism. METHODS: A total of 35 SD rats were randomized into a sham BCP group (=6), a BCP group (=7), a MT group (=7), a BNA+EA group (=8) and a shame BNA group (=7). Except of the sham BCP group, cancer cell inoculation operation at left tibia was given in the other 4 groups to establish the bone cancer pain model. In the MT group, the BNA+EA group and the shame BNA group, intraperitoneal injection of morphine hydrochloride was given to establish the morphine tolerance model. After the operation, bone-nearby acupuncture combined with electroacupuncture was applied at "Zusanli" (ST 36) and "Kunlun" (BL 60) in the BNA+EA group, with dilatational wave, 2 Hz/100 Hz in frequency, 0.5 to 1.5 mA in intensity. Intervention in the shame BNA group was applied at the same time and acupoints as those in the BNA+EA group, the needles were pierced the skin without any electrical stimulation. The needles were retained for 30 min, once a day for continuous 7 days in both BNA+EA and shame BNA groups. Before and 10, 11, 15, 22 days after the operation, the left paw withdrawal threshold (PWT) was measured in the 5 groups. The levels of HDAC1, HDAC2 and MOR in DRG were detected by Western blot. RESULTS: Ten days after the cancer cell inoculation operation, the PWT of the BCP, MT, BNA+EA and sham BNA groups was decreased compared with the sham BCP group (<0.01). Eleven days after the operation, the PWT of the MT, BNA+EA and sham BNA groups was increased compared with the BCP group (<0.01). Twenty-two days after the operation, the difference was no significant between the BCP group and MT group (>0.05); the PWT of the BNA+EA group was increased compared with the MT and sham BNA group (<0.01). In the BCP group, the DRG levels of HDAC1 and HDCA2 were increased, while the level of MOR was decreased compared with the sham BCP group (<0.05, <0.01). In the MT group, the DRG level of HDAC1 was increased compared with the BCP group (<0.05). In the BNA+EA group, the DRG level of HDAC1 was decreased compared with the MT group and the sham BNA group (<0.01, <0.05), while the level of MOR was increased (<0.01). CONCLUSION Early intervention of bone-nearby acupuncture combined with electroacupuncture can relieve the morphine tolerance in bone cancer pain rats, it may relate to down-regulating the expression of HDAC1 and up-regulating the expression of MOR in the dorsal root ganglia.
Acupuncture Points ; Animals ; Bone Neoplasms ; complications ; Cancer Pain ; therapy ; Drug Tolerance ; Electroacupuncture ; Ganglia, Spinal ; metabolism ; Histone Deacetylases ; metabolism ; Morphine ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid, mu ; metabolism

Neuraxial opioid administration is one of the most common methods of anesthesia and analgesia,while itching is the most troublesome adverse effect.The current treatments for neuraxial opioid-induced pruritus still have certain limitations.This article reviews the current treatments and basic scientific findings(including neurotransmitters,opioid receptors,and signaling pathways)of pruritus caused by neuraxial opioids.Based on our recent findings on N-methyl-D-aspartate(NMDA)receptors and pruritus caused by neuraxial opioids,we provide new ideas for the treatment of itching caused by neuraxial opioids.Since NMDA receptors may play a key role in neuraxial opioid-induced pruritus,NMDA receptor antagonists can have certain therapeutic advantages.
Analgesics, Opioid ; Humans ; Pruritus ; Receptors, N-Methyl-D-Aspartate

OBJECTIVE: To investigate the role of zinc-fingers and homeoboxes 2 (ZHX2) in regulating μ-opioid receptor expression in the dorsal root ganglion (DRG) in mice with peripheral nerve injury-induced pain hypersensitivity. METHODS: Forty-eight male adult C57BL6J mice were randomized into 4 groups and subjected to chronic constriction injury (CCI) of the sciatic nerve or sham operation followed by microinjection of a specific small interfering RNA (siRNA) of ZHX2 or a negative control siRNA sequence (siNC) into the DRG. Seven days later, the mice were examined for changes in the hind paw withdrawal frequency (PWF), after which the DRG tissue was collected for detecting the expressions of μ-opioid receptor at the mRNA and protein levels using RT-qPCR and Western blotting. In another experiment, the DRG tissues were collected from 6 mice (21-day-old) for primary culture of the DRG neurons, which were transfected with ZHX2 siRNA or the siNC to observe the changes in the expressions of ZHX2 and μ-pioid receptor. RESULTS: Microinjection of ZHX2 siRNA into the ipsilateral L3 and L4 DRGs significantly reversed CCI-induced μ-pioid receptor downregulation in the injured DRG and alleviated CCI-induced mechanical allodynia in the mice. In the cell experiment, ZHX2 knockdown obviously upregulated the mRNA and protein expressions of opioid receptor in the primary cultured DRG neurons. CONCLUSIONS ZHX2 knockdown in the DRG reverses CCI-induced down-regulation of μ opioid receptor to alleviate periphery nerve injury-induced pain hypersensitivity in mice.
Animals ; Ganglia, Spinal ; Homeodomain Proteins ; Hyperalgesia ; Male ; Mice ; Neuralgia ; Rats, Sprague-Dawley ; Receptors, Opioid, mu

BACKGROUND: This study was performed in order to examine the effect of intrathecal sec-O-glucosylhamaudol (SOG), an extract from the root of the Peucedanum japonicum Thunb., on incisional pain in a rat model. METHODS: The intrathecal catheter was inserted in male Sprague-Dawley rats (n = 55). The postoperative pain model was made and paw withdrawal thresholds (PWTs) were evaluated. Rats were randomly treated with a vehicle (70% dimethyl sulfoxide) and SOG (10 μg, 30 μg, 100 μg, and 300 μg) intrathecally, and PWT was observed for four hours. Dose-responsiveness and ED50 values were calculated. Naloxone was administered 10 min prior to treatment of SOG 300 μg in order to assess the involvement of SOG with an opioid receptor. The protein levels of the δ-opioid receptor, κ-opioid receptor, and μ-opioid receptor (MOR) were analyzed by Western blotting of the spinal cord. RESULTS: Intrathecal SOG significantly increased PWT in a dose-dependent manner. Maximum effects were achieved at a dose of 300 μg at 60 min after SOG administration, and the maximal possible effect was 85.35% at that time. The medial effective dose of intrathecal SOG was 191.3 μg (95% confidence interval, 102.3–357.8). The antinociceptive effects of SOG (300 μg) were significantly reverted until 60 min by naloxone. The protein levels of MOR were decreased by administration of SOG. CONCLUSIONS: Intrathecal SOG showed a significant antinociceptive effect on the postoperative pain model and reverted by naloxone. The expression of MOR were changed by SOG. The effects of SOG seem to involve the MOR.
Analgesia ; Animals ; Blotting, Western ; Catheters ; Dimethyl Sulfoxide ; Humans ; Hyperalgesia ; Male ; Models, Animal ; Naloxone ; Nociceptive Pain ; Pain, Postoperative ; Rats ; Rats, Sprague-Dawley ; Receptors, Opioid ; Spinal Cord

BACKGROUND: Pain is a complex mechanism which involves different systems, including the opioidergic and GABAergic systems. Due to the side effects of chemical analgesic agents, attention toward natural agents have been increased. Artemisinin is an herbal compound with widespread modern and traditional therapeutic indications, which its interaction with the GABAergic system and antinoniceptive effects on neuropathic pain have shown. Therefore, this study was designed to evaluate the antinociceptive effects of artemisinin during inflammatory pain and interaction with the GABAergic and opioidergic systems by using a writhing response test. METHODS: On the whole, 198 adult male albino mice were used in 4 experiments, including 9 groups (n = 6) each with three replicates, by intraperitoneal (i.p.) administration of artemisinin (2.5, 5, and 10 mg/kg), naloxone (2 mg/kg), bicuculline (2 mg/kg), saclofen (2 mg/kg), indomethacin (5 mg/kg), and ethanol (10 mL/kg). Writhing test responses were induced by i.p. injection of 10 mL/kg of 0.6% acetic acid, and the percentage of writhing inhibition was recorded. RESULTS: Results showed significant dose dependent anti-nociceptive effects from artemisinin which, at a 10 mg/kg dose, was statistically similar to indomethacin. Neither saclofen nor naloxone had antinociceptive effects and did not antagonize antinociceptive effects of artemisinin, whereas bicuculline significantly inhibited the antinocicptive effect of artemisinin. CONCLUSIONS: It seems that antinocicptive effects of artemisinin are mediated by GABAA receptors.
Acetic Acid ; Adult ; Analgesics ; Analgesics, Opioid ; Animals ; Bicuculline ; Ethanol ; gamma-Aminobutyric Acid ; Humans ; Indomethacin ; Inflammation ; Male ; Mice ; Naloxone ; Neuralgia ; Receptors, GABA

Nociceptin/orphanin FQ (N/OFQ) and its receptor, nociceptin opioid peptide (NOP) receptor, are localized in brain areas implicated in depression including the amygdala, bed nucleus of the stria terminalis, habenula, and monoaminergic nuclei in the brain stem. N/OFQ inhibits neuronal excitability of monoaminergic neurons and monoamine release from their terminals by activation of G protein-coupled inwardly rectifying K⁺ channels and inhibition of voltage sensitive calcium channels, respectively. Therefore, NOP receptor antagonists have been proposed as a potential antidepressant. Indeed, mounting evidence shows that NOP receptor antagonists have antidepressant-like effects in various preclinical animal models of depression, and recent clinical studies again confirmed the idea that blockade of NOP receptor signaling could provide a novel strategy for the treatment of depression. In this review, we describe the pharmacological effects of N/OFQ in relation to depression and explore the possible mechanism of NOP receptor antagonists as potential antidepressants.
Amygdala ; Antidepressive Agents ; Brain ; Brain Stem ; Calcium Channels ; Depression ; Habenula ; Models, Animal ; Neurons ; Neuropeptides ; Opioid Peptides ; Receptors, Drug ; Septal Nuclei