• Journal of Life Science
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• v.23 no.2
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• pp.157-166
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• 2013

This study aimed to investigate whether nociceptin contributes to the alterations in cerebral blood flow (CBF) regulation following postnatal exposure to ethanol in Sprague-Dawley rats. Animals received ethanol twice a day, 2 hr apart, on postnatal 6, 7 and 8 days. The changes in regional CBF (rCBF) in response to the changes in mean arterial blood pressure were determined at 4-, 8-, and 12-week of age by laser-Doppler flowmetry. Hypotension was induced by the gradual withdrawal of blood from arterial catheter, and the reversal of blood pressure was produced by the reinfusion of blood. Expression of nociceptin-like immunoreactivity was determined in dura mater and cerebral cortex using immunohistochemistry. Postnatal exposure to ethanol almost abolished the autoregulation of rCBF in all age groups. Pretreatment with nociceptin but not with [$Nphe^1$]nociceptin(1-13)$NH_2$, a selective competitive nociceptin receptor antagonist, 5 min prior to ethanol administration preserved the autoregulation of rCBF in all age groups. Postnatal exposure to ethanol markedly increased the expressions of nociceptin-like immunoreactivity in the dura mater and cerebral cortex, both of which were significantly inhibited by pretreatment with 7-nitroindazole monosodium salt as well as aminoguanidine 5 min prior to ethanol administration in all age groups. The values of arterial blood gas analysis were not significantly different from the basal levels in all groups. These results suggest that nociceptin deeply contributes to the compensatory mechanisms for the nitric oxide-dependent alterations in CBF autoregulation following postnatal exposure to ethanol.

• Biomedical Science Letters
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• v.11 no.3
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• pp.375-382
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• 2005

This study aimed to investigate whether nociceptin is implicated in the, trigeminovascular responses to electrical stimulation of trigeminal ganglion in rats. An open cranial window was prepared on the right parietal bone of male Sprague-Dawley rats. Trigeminovascular system was stimulated by electrical stimulation of trigeminal ganglion (ETS; 5ms, 5Hz, 3V). Neonatal capsaicin treatment was performed with subcutaneous administration of capsaicin (50mg/kg) within the first 24 hours after birth. Changes in regional cerebral blood flow were continuously measured through the cranial window by laser-Doppler flowmetry, and the expression of nociceptin-like immunoreactivity was determined by immunohistochemistry. ETS caused increases in regional blood flow of pial arteriole in a voltage-dependent manner. ETS markedly and voltage-dependently increased the expression of nociceptin-like immunoreactivity in dura mater ipsilateral rather than contralateral to ETS. The nociceptin-like immunoreactivity was markedly reduced by pretreatments with calcitonin gene-related peptide(8-37) ($CGRP_{8-37},\;a\;CGRP_1$ receptor antagonist), L-733060 (a $NK_1$ receptor antagonist), and $[Nphe^1]$ nociceptin(1-13)$NH_2$ (a selective and competitive nociceptin receptor antagonist) as well as by neonatal capsaicin treatment. These results suggest that the electrical stimulation of trigeminal ganglion causes prominent expression of nociceptin within dura mater, in which not only neuropeptides inducing substance P and CGRP but also nociceptin are implicated in the trigeminovascular responses to electrical trigeminal ganglion stimulation.

• Biomedical Science Letters
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• v.11 no.2
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• pp.201-209
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• 2005

This study aimed to investigate the cerebroprotective effect of nociceptin on transient focal cerebral ischemia in Sprague-Dawley rats by determining the changes in regional cerebral blood flow (rCBF) and the infarct size. Right middle cerebral artery (MCA) was occluded for 2 hours, and thereafter was followed by reperfusion by an intraluminal monofilament technique. An open cranial window was made on the right parietal bone for determination of continuous changes in rCBF by laser-Doppler flowmetry. The infarct size was morphometrically determined using the 2,3,5-triphenyltetrazolium chloride technique. In normal rats, nociceptin ($0.01\~100\;nmol/kg$, Lv.) increased rCBF and decreased cerebral arterial resistance in a dose-dependent manner. Systemic arterial blood pressure was little affected by nociceptin at the doses of 0.01 and 0.1nmol/kg, but dose-dependently reduced at the doses of 1 nmol/kg or more. In transient cerebral ischemic rats, nociceptin ($0.01\~0.1$ nmol/kg, i.p.) significantly attenuated the postischemic cerebral hyperemia, and progressively increased rCBF. The improving effect of nociceptin on the postischemic rCBF response was markedly blocked by pretreatment with $[Nphe^1]nociceptin(1-13)NH_2$ (1 nmol/kg, i.p.), a selective nociceptin receptor antagonist, but not by naloxone ($3{\mu}mol/kg$, i.p.), a selective opioid receptor antagonist. The cerebral infarct size was significantly reduced by nociceptin ($0.01\~0.1$ nmol/kg) administered i.p. 5 min after MCA occlusion in transient cerebral ischemia of 2-hour MCA occlusion and 22-hour reperfusiion. It is suggested that nociceptin improves the postischemic cerebral hemodynamics and thereby has a cerebroprotective effect in transient focal cerebral ischemia.

• The Korean Journal of Physiology and Pharmacology
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• v.23 no.6
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• pp.427-448
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• 2019

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.

• Korean Journal of Acupuncture
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• v.28 no.2
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• pp.37-47
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• 2011

Objectives : We have studied the effects of GaAlAs (808 nm) low level laser therapy (LLLT) and acupuncture at BL40 on neuropathic pain in rats induced by lumbar spinal nerve 5 ligation. Methods : To produce the model of neuropathic pain, under isoflurane 2.5% anesthesia, the lumbar spinal nerve 5 was ligated by 6-0 silk thread. After neuropathic surgery, we examined if the animals exhibited the behavioral sign of allodynia. The allodynia was assessed by stimulating the medial malleolus with von Frey filament and acetone. Three weeks after the neuropathic surgery, GaAlAs (808 nm) low level laser and acupuncture was inserted at BL40 once a day for 6 days. We examined the withdrawal response of neuropathic rats' legs by von Frey filament and acetone stimulation. And also the author examined c-Fos, nociceptin and nociceptin receptor in the midbrain central gray of neuropathic rats. Results : The GaAlAs (808 nm) low level laser therapy and acupuncture at BL40 decreased the withdrawal response of mechanical allodynia that assessed with von Frey filament in LLLT group on 5 and 6 times and with acetone in AT group and LLLT on 6times. The LLLT and acupuncture at BL40 decreased the c-Fos protein expression in AT and LLLT groups. The 808 nm LLLT and acupuncture at BL40 decreased the nociceptin protein and nociceptin receptor protein in LLLT group. Conclusions : We have noticed that GaAlAs (808 nm) LLLT and acupuncture at BL40 decreased mechanical allodynia in the model of neuropathic pain. c-Fos, nociceptin and nociceptin receptor expression in the central gray of that group was also decreased. This study can be used as a basic resource on a study and a treatment of pain.

• Journal of Acupuncture Research
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• v.27 no.5
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• pp.13-24
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• 2010

Objectives : This study was designed to investigate the effects of bee venom acupuncture at Shinsu($BL_{23}$) and Daejangsu($BL_{25}$) on neuropathic pain induced by tibial and sural nerve injury in rats. Methods : Neuropathic pain model was made by partial resection of tibial and sural nerve. Three weeks after the neuropathic surgery, bee venom acupuncture was firstly injected at $BL_{23}$ and $BL_{25}$, then we measured withdrawal responses induced by von Frey filament and acetone stimulation. Bee venom acupunctures were injected 6times on every 2days. Measurement of withdrawal responses were conducted on the same days. After bee venom acupuncture injection, expression levels of c-Fos, nocieptin and KOR-3 were observed through using immunohistochemistry. Results : In this experiment, bee venom acupunctures at $BL_{23}$ and $BL_{25}$ decreased levels of withdrawal responses induced by von Frey filament and acetone stimulation respectively. In addtion, expression levels of c-Fos, nociceptin and KOR-3 in central gray part of brain in rats were decreased by bee venom acupuncture. Conclusions : These results imply that bee venom acupuncture was useful to treat patients with neuropathic pain, and related mechanisms were involved in opioid and their receptors such as nociceptin and KOR-3.

• Journal of Acupuncture Research
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• v.24 no.5
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• pp.137-150
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• 2007

Objectives : To find effects of acupuncture, electro-acupuncture, low level He-Ne laser therapy(LLLT) at $TE_5$, $GB_{41}$ in the neuropathic pain. We made experiment on rats ligated L5 spinal nerve like general herniation of nucleus pulposus(HNP). Methods : A model of neuropathic pain was made by isolating Left 5th lumbar spinal nerve of rats. Three days after the neuropathic surgery, acupuncture and LLLT, electro-acupuncture was injected at $TE_5$, $GB_{41}$ one time a day for a week. Each group was divided two. one is opposite side performed the surgery which is right, another is left side performed the surgery. After that, the author examined the withdrawal response of neuropathic rats' legs by van Frey filament and acetone stimulation. And also the author examined c-Fos, Nociceptin and KOR-3 in the midbrain central gray of neuropathic rats. Results : As we have observed the effect of mechanical allodynia, LT-R group were diminished on 6th day compared with control group, EA-L group, EA-R group and LT-L group were diminished on 7th day compared with control group. As we have observed the effect of cold allodynia, EA-R group were diminished on 6th day, 7th day compared with control group. As we have observed the effect of activity of c-Fos in the central gray part, EA-R group and LT-R group were diminished compared with control group. As we have observed the effect of activity of Nociceptin in the central gray part, EA-R group were a little increased compared with control group but it is not reliability. As we have observed the effect of activity of KOR-3 in the central gray part, EA-R group were significantly increased compared with control group. Conclusions : We have noticed that effect of acupuncture at opposite side of sickness and powerful stimulation could be more effective, because of EA-R group have more controllable effect all test we have done on the other hand EA-L group have only effect on mechanical allodynia. This study can be used in clinical therapy for neuropathic pain. But it is not reliability that Nociceptin have effectively to control pain. Therefore We have to follow up about that.

• Korean Journal of Acupuncture
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• v.22 no.2
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• pp.9-24
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• 2005

Objective: We have studied the effects of acupuncture and low level He-Ne laser therapy(LLLT) at $SI_3$, $BL_{40}$ on the tibial, sural nerve injury due to sports-damage or traffic accident and L5 spinal nerve ligature model like general herniation of nucleus pulposus(HNP) in a rat of neuopathic pain. Methods: A model of neuropathic pain was made by injuring tibial nerve and sural nerve while common peroneal nerve was maintained. Also, it was made by isolating left 5th lumbar spinal nerve. Three weeks after the neuropathic surgery, acupuncture and LLLT was injected at $SI_3$,$BL_{40}$ one time a day for one week. LLLT was divided three groups, that is LLLT-1(5mW), LLLT-2(10mW) and LLLT-3(30mW). After that, we examined the withdrawal response of neuropathic rats' legs by Von frey filament and acetone stimulation. And also we examined c-Fos, Nocieptin and KOR-3 in the midbrain central gray of neuropathic rats. Results: As we have observed the effect of mechanical allodynia, LLLT-3 group were diminished on 4 day, 5 day, 6 day and 7 day in the resection model compared with control model, LLLT-1 group were diminished on 5 day, LLLT-2 group were diminished on 3 day and 6 day, LLLT-3 group were diminished on 3 day, 4 day, 5 day, 6 day and 7 day in connected model compared with control group. As we have observed the effect of cold allodynia, LLLT-3 group were diminished on 7 day in the resection model compared with control model, LLLT-1 group were diminished on 6 day, 7 day, LLLT-3 group were diminished on 7 day in connected model compared with control group. As we have observed the effect of activity of c-Fos in the central gray part, LLLT-3 were diminished in resection model compared with control group, LLLT-1 group were diminished in connected model compared with control group. As we have observed the effect of activity of Nociceptin in the central gray part, resection model were not increased compared with control group, LLLT-1 group and LLLT-3 group were increased in connected model compared with control model. As we have observed the effect of activity of KOR-3 in the central gray part, resection model were not increased compared with control group, LLLT-3 group were increased in connected model compared with control model. Conclusions: We have noticed that LLLT-1 and LLLT-3 group have more controllable effect than acupuncture group. This study can be used in clinical therapy for neuropathic pain. But it is not reliability that Nociceptin and KOR-3 have effectively to control pain. Therefore We have to follow up about that.

• Journal of Acupuncture Research
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• v.30 no.3
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• pp.125-134
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• 2013

Objectives : We studied the effects of electro and laser acupuncture treatment with $GB_{39}$ and $GB_{34}$ on neuropathic pain in rats induced by tibial and sural nerve ligation. Methods : To produce the model of neuropathic pain, the tibial and sural nerves of rats were ligated by a 6-0 silk thread. Three days after the neuropathic surgery, only electro acupuncture(EA), electro acupuncture and 830 nm laser acupuncture(EA-LA-1), and electro acupuncture and 904 nm laser acupuncture(EA-LA-2) were treated with $GB_{39}$ and $GB_{34}$ twice a week for 8 weeks. We observed the withdrawal response of neuropathic rats' legs by von Frey filament and acetone stimulation. We also observed c-fos and nocieptin on the central gray area in the midbrain of neuropathic rats. Results : As we observed the effect of mechanical allodynia, the EA and EA-LA-1 groups in 5 and 6 weeks and the EA-LA-2 group in 6 weeks increased significantly compared with the control group. As for the effect of c-fos activity in the central gray region, the EA, EA-LA-1, and EA-LA-2 groups decreased significantly compared with the control group. The EA-LA-2 group increased significantly compared with the control group as regards the effect of nociceptin activity in the central gray region. Conclusions : We noticed the synergic effect of electro and laser acupuncture treatment because the EA-LA-1 and EA-LA-2 groups had more controllable effect compared with the control group. This study can be used in clinical therapy for neuropathic pain.

• The Korean Journal of Pain
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• v.35 no.3
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• pp.261-270
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• 2022

Background: The rostral ventromedial medulla (RVM) is a critical region for the management of nociception. The RVM is also involved in learning and memory processes due to its relationship with the hippocampus. The purpose of the present study was to investigate the molecular mechanisms behind orexin-A signaling in the RVM and hippocampus's effects on capsaicin-induced pulpal nociception and cognitive impairments in rats. Methods: Capsaicin (100 g) was applied intradentally to male Wistar rats to induce inflammatory pulpal nociception. Orexin-A and an orexin-1 receptor antagonist (SB-334867) were then microinjected into the RVM. Immunoblotting and immunofluorescence staining were used to check the levels of cyclooxygenase-2 (COX-2) and brain-derived neurotrophic factor (BDNF) in the RVM and hippocampus. Results: Interdental capsaicin treatment resulted in nociceptive responses as well as a reduction in spatial learning and memory. Additionally, it resulted in decreased BDNF and increased COX-2 expression levels. Orexin-A administration (50 pmol/1 µL/rat) could reverse such molecular changes. SB-334867 microinjection (80 nM/1 µL/rat) suppressed orexin's effects. Conclusions: Orexin-A signaling in the RVM and hippocampus modulates capsaicin-induced pulpal nociception in male rats by increasing BDNF expression and decreasing COX-2 expression.