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Richard Bandler - One of the best experts on this subject based on the ideXlab platform.
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noxious activation of spinal or vagal afferents evokes distinct patterns of fos like immunoreactivity in the Ventrolateral Periaqueductal Gray of unanaesthetised rats
Brain Research, 2002Co-Authors: Kevin A. Keay, Colin I Clement, Richard Bandler, Luke A Henderson, W M Matar, David HeslopAbstract:Abstract The consequences of a severe traumatic injury—deep pain and haemorrhage—usually evoke a passive emotional coping reaction characterised by: quiescence and immobility, decreased vigilance, hypotension and bradycardia. Results of studies utilising microinjections of excitatory amino acids suggest that passive coping reactions are mediated, at least in part, by activation of the midbrain, Ventrolateral Periaqueductal Gray (vlPAG) region. Further, experiments in anaesthetised rats, using the expression of the immediate-early gene, c-fos, as a marker of neuronal activation, report that pain arising from muscles, joints or viscera selectively activates the vlPAG. Anaesthesia alone, however, evokes substantial Fos-like immunoreactivity (IR) within the vlPAG and this may have obscured any differences in patterns of Fos expression following noxious deep somatic versus noxious visceral activation. In these experiments, in unanaesthetised rats, the effects of noxious spinal versus noxious vagal primary afferent activation were re-examined and distinct rostrocaudal patterns of Fos-expression were observed. Specifically: (i) injection of algesic substances into muscle, which preferentially activates spinal afferents, evoked Fos expression predominantly within the caudal vlPAG; whereas, (ii) noxious manipulations whose effects are mediated by (cardiopulmonary) vagal activation evoked preferential Fos-expression within the rostral vlPAG. On the other hand, hypotensive haemorrhage evoked substantial Fos expression along the entire rostrocaudal extent of the vlPAG, a finding which fits with suggestions that haemorrhagic shock is triggered by a combination of: (i) spinally-relayed nociceptive signals originating from ischaemic tissue, and (ii) vagally-relayed signals reflecting poor cardiac filling.
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spinal sources of noxious visceral and noxious deep somatic afferent drive onto the Ventrolateral Periaqueductal Gray of the rat
The Journal of Comparative Neurology, 2000Co-Authors: Colin I Clement, Kevin A. Keay, Katherine Podzebenko, Brent D Gordon, Richard BandlerAbstract:Studies utilizing the expression of Fos protein as a marker of neuronal activation have revealed that pain of deep somatic or visceral origin selectively activates the Ventrolateral Periaqueductal Gray (vlPAG). Previous anatomical tracing studies revealed that spinal afferents to the vlPAG arose from the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus at all spinal segmental levels, with approximately 50% of vlPAG-projecting spinal neurons found within the upper cervical spinal cord. This study utilized detection of Fos protein to determine the specific populations of vlPAG-projecting spinal neurons activated by noxious deep somatic or noxious visceral stimulation. Pain of cardiac or peritoneal (i.e., visceral) origin activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the thoracic cord, whereas pain of hindlimb (i.e., deep somatic) origin activated neurons in the same laminar regions but in the lumbosacral cord. Each of these deep noxious manipulations also activated neurons in the superficial and deep dorsal horn and nucleus of the dorsolateral funiculus of the upper cervical spinal cord. In a second set of experiments, the combination of retrograde tracing and Fos immunohistochemistry revealed that vlPAG-projecting spinal neurons activated by deep somatic pain were located in both the upper cervical and lumbosacral cord, whereas those activated by visceral pain were restricted to the thoracic spinal cord. Thus pain arising from visceral versus deep somatic body regions influences neural activity within the vlPAG via distinct spinal pathways. The findings also highlight the potential significance of the upper cervical cord in integrating pain arising from deep structures throughout the body.
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muscle pain activates a direct projection from Ventrolateral Periaqueductal Gray to rostral Ventrolateral medulla in rats
Neuroscience Letters, 2000Co-Authors: Kevin A. Keay, Richard BandlerAbstract:Activation of the Ventrolateral Periaqueductal Gray (vlPAG) evokes a reaction of quiescence, immobility, hypotension and bradycardia. Pain of deep somatic or visceral origin also often triggers a reaction of quiescence, immobility, hypotension and bradycardia and further, evokes a selective increase in immediate-early-gene (c-Fos) expression within the vlPAG. Vasodepression evoked from the vlPAG is thought to be mediated by an inhibition of presympathetic neurons within the rostral Ventrolateral medulla (RVLM). In this study the prior injection of retrograde tracer into the RVLM was combined with the use of Fos expression as a marker of neuronal activation, to determine if deep (muscle) pain-evoked vasodepression could be mediated by a direct vlPAG-RVLM pathway. It was revealed that intramuscular injection of formalin, in the anaesthetised rat, evoked a significant increase in Fos expression within the caudal vlPAG, and that approximately 25% of the Fos-immunoreactive neurons projected to the RVLM.
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medullary catecholaminergic projections to the Ventrolateral Periaqueductal Gray region activated by halothane anaesthesia
Neuroscience, 1998Co-Authors: Colin I Clement, Kevin A. Keay, Richard BandlerAbstract:Abstract Under anaesthesia, blood loss and deep pain can evoke a premature, centrally-mediated sympathoinhibition leading to decompensated shock and sometimes even death. The central circuits evoking premature vasodepressor syncope are unknown, although medullary catecholaminergic pathways have been implicated. The Ventrolateral Periaqueductal Gray region is one of only three brain regions in which catecholamine content is increased during halothane anaesthesia. The Ventrolateral Periaqueductal Gray also contains neurons which are selectively activated by blood loss and deep pain, and recent work from our laboratory has suggested that it is a pivotal structure in central sympathoinhibitory circuits. Using retrograde tracing techniques combined with the immunohistochemical detection of: (i) the catecholamine synthetic enzyme, tyrosine hydroxylase and (ii) the protein product of the immediate-early gene c-fos as a marker of neuronal activation; the results of this study indicate that catecholaminergic projections from the A1, C1 and C2 regions of the medulla to the Ventrolateral Periaqueductal Gray are activated by halothane anaesthesia. These data are consistent with the hypotheses that ascending catecholaminergic projections to the Ventrolateral Periaqueductal Gray: (i) are a component of the central neural circuitry responsible for the sympathoinhibitory effects of halothane anaesthesia, and (ii) may contribute to the premature elicitation of vasodepressor syncope following blood loss and deep pain under conditions of anaesthesia.
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vascular head pain selectively activates Ventrolateral Periaqueductal Gray in the cat
Neuroscience Letters, 1998Co-Authors: Kevin A. Keay, Richard BandlerAbstract:Electrical stimulation of the superior sagittal sinus is an experimental model of migraine which activates neurons within the upper cervical spinal cord. The Ventrolateral Periaqueductal Gray has been proposed as an integrative centre for the autonomic and behavioural responses to deep pain and also receives significant inputs from the upper cervical spinal cord. The noxious-stimulation evoked expression of the immediate-early gene c-fos, was used to determine if sagittal sinus stimulation activates neurons of the Ventrolateral Periaqueductal Gray. The superior sagittal sinus was stimulated in anesthetised cats and Fos-protein was detected in coronal brain sections using standard avidin-biotin immunohistochemistry. A pattern of Fos-positive cells restricted to the caudal Ventrolateral Periaqueductal Gray was revealed suggesting that this region may mediate the pattern of somatic and autonomic responses characteristic of migraine.
Carmela Parenti - One of the best experts on this subject based on the ideXlab platform.
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the functional antiopioid action of the Ventrolateral Periaqueductal Gray nociceptin orphanin fq and nociceptin receptor system underlies damgo analgesic tolerance
Pharmacology, 2010Co-Authors: Carmela Parenti, Giovanna M. ScotoAbstract:Nociceptin/Orphanin FQ (N/OFQ) counteracts supraspinal opioid effects and plays a role in antinociceptive morphine tolerance. Therefore, in the present study, the selective µ-opioid agonist [D-Ala2-NMe-Phe4-Gly-ol5]-enkephalin (DAMGO) was used. Repeated injection of DAMGO (1 µg/ 1 µl) into the Ventrolateral Periaqueductal Gray (vlPAG), a key site for the development of opioid tolerance, induced analgesia that lasted up to 3 days. In DAMGO-tolerant rats, injection of the N/OFQ antagonist (±)-J 113397 (4 µg/1 µl), into the same site, restored the antinociceptive effect of DAMGO. If (±)-J 113397 treatment preceded each DAMGO injection, tolerance did not develop. Inhibition of N/OFQ signaling can reverse and prevent the development of DAMGO tolerance in the vlPAG. The results confirm that N/OFQ acts as a functional opioid antagonist.
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selective inhibition of the nop receptor in the Ventrolateral Periaqueductal Gray attenuates the development and the expression of tolerance to morphine induced antinociception in rats
Peptides, 2010Co-Authors: G M Scoto, Attilio Iemolo, Giuseppina Arico, Giuseppe Ronsisvalle, Carmela ParentiAbstract:The Ventrolateral Periaqueductal Gray (vlPAG) is a major site of opioid analgesic action and a key locus for the development of morphine tolerance. Previous experimental evidence supports the hypothesis that the brain synthesizes and secretes neuropeptides, which act as a part of the homeostatic system to attenuate the effects of morphine and endogenous opioid peptides. Among the known antiopioid peptides, nociceptin/orphanin FQ (N/OFQ) has been shown to inhibit various opioid effects, especially analgesia. The present study investigated the effect of NOP receptor blockade on the tolerance to morphine antinociception in the vlPAG. Systemic morphine (10mg/kg s.c. twice per day) induced an antinociceptive effect that diminished significantly on the third day when tolerance developed, as quantified by the tail flick and the hot plate tests. Intra vlPAG (i.vlPAG) administration of the NOP receptor antagonist (+/-)-J 113397 restored the opioid's analgesic effect. When (+/-)-J 113397 was administered beginning the first day preceding each morphine administration, tolerance did not develop, but it appeared if the NOP antagonist had been suspended. These data suggest that the N/OFQ in the vlPAG may play a key role in opioid-induced antinociceptive tolerance.
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involvement of the nociceptin orphanin fq nop receptor system in the Ventrolateral Periaqueductal Gray following mechanical allodynia in chronic pain
Life Sciences, 2009Co-Authors: Giovanna M. Scoto, Giuseppina Arico, Simone Ronsisvalle, Attilio Iemolo, Carmela ParentiAbstract:Abstract Aims It has been well documented that Ventrolateral Periaqueductal Gray (vlPAG) matter is a crucial component of the descending pain modulatory system in the chronic pain condition. The aim of the present study was to identify the role of the vlPAG Nociceptin/Orphanin FQ/NOP receptor system in allodynia, a nociceptive behavioral response associated with chronic pain. Main methods We used two animal models of persistent pain: chronic constriction injury (CCI) and inflammation induced by carrageenan. In each, Nociceptin/Orphanin FQ transmission was abolished using UFP-101, a selective NOP receptor antagonist, which was injected into the vlPAG at a dose of 18 µg/1 µl/rat. Key findings We found that treatment with the NOP antagonist reversed the decrease in allodynic threshold in CCI rats fourteen days after the ligature, which was the timepoint of the greatest reduction in threshold. Moreover, UFP-101 administered immediately prior to or 2 h after intra plantar (i.pl.) carrageenan injection prevented or reversed, respectively, allodynic behavior in rats with inflammation. Significance Our findings support the hypothesis that the endogenous Nociceptin/Orphanin FQ/NOP receptor system is tonically active at the vlPAG level during neuropathic states or carrageenan inflammation.
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blockade of the nociceptin orphanin fq nop receptor system in the rat Ventrolateral Periaqueductal Gray potentiates damgo analgesia
Peptides, 2007Co-Authors: Giovanna M. Scoto, Giuseppina Arico, Simone Ronsisvalle, Carmela ParentiAbstract:Nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are involved in various biological functions including pain. High density of NOP receptor has been found in the Ventrolateral Periaqueductal Gray (vlPAG), the main output pathway involved in descending pain-control system. The aim of our work was to evaluate the involvement of the N/OFQ/NOP system in the modulation of MOP analgesia in the rat vlPAG using UFP-101, a selective NOP antagonist. N/OFQ significantly blocked DAMGO (a selective MOP agonist) analgesia, while UFP-101 enhanced the effect of the opioid given at a subanalgesic dose. These results confirm our hypothesis of an antiopioid role for N/OFQ in the vlPAG.
Richard J. Bodnar - One of the best experts on this subject based on the ideXlab platform.
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neonatal and adult gonadal hormone manipulations enhance morphine analgesia elicited from the Ventrolateral Periaqueductal Gray in female rats
International Journal of Neuroscience, 2010Co-Authors: Giuseppe Cataldo, S Y Bernal, S Rozengurtel, Kay L Medina, Richard J. BodnarAbstract:ABSTRACTMale rodents displayed greater magnitudes of analgesia following systemic, ventricular, and intracerebral administration of μ-opioid receptor agonists than female rodents. Whereas neonatal castration of male rat pups produced reductions in systemic and central morphine analgesia as adults, neonatal androgenization of female rat pups treated with testosterone propionate (TP) displayed enhancements in systemic and central morphine analgesia as adults. Adult gonadectomy minimally affected μ-opioid analgesia, except if less potent μ agonists were employed, or if morphine was directly administered into the Ventrolateral Periaqueductal Gray (vlPAG). Adult ovariectomy failed to appreciably alter the enhanced analgesia following systemic morphine in female rats with neonatal androgenization. Because the vlPAG elicited morphine analgesia that was sensitive to both neonatal and adult gonadal hormone manipulations, the present study examined morphine analgesia elicited from the vlPAG in female rats receiving...
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estrus phase differences in female rats in morphine antinociception elicited from the Ventrolateral Periaqueductal Gray
International Journal of Neuroscience, 2007Co-Authors: Randi Shane, S Rozengurtel, S Y Bernal, Richard J. BodnarAbstract:Male rodents display greater systemic morphine antinociception than females which show their most marked effects during late diestrus or proestrus. Morphine (1–2.5 μg) antinociception on the tail-f...
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reciprocal interactions between the amygdala and Ventrolateral Periaqueductal Gray in mediating of q n1 17 induced analgesia in the rat
Brain Research, 2003Co-Authors: Randi Shane, Jazmin Acosta, Grace C Rossi, Richard J. BodnarAbstract:Abstract The opioid peptide, Orphanin FQ/nociceptin (OFQ/N 1–17 ) , its active fragments, and a related precursor peptide each produce analgesia following microinjection into the amygdala of rats. OFQ/N 1–17 -induced analgesia elicited from the amygdala is blocked by amygdala pretreatment of either general, μ, κ, or δ-opioid antagonists even though OFQ/N 1–17 binds poorly to these receptor subtypes, and the antagonists bind poorly to the ORL-1/KOR-3 receptor. Agonists at μ and κ opioid receptors as well as β-endorphin each produce analgesia elicited from the amygdala that is blocked by opioid antagonist pretreatment in the Ventrolateral Periaqueductal Gray (vlPAG) of rats. The present study examined whether pretreatment of general and selective opioid antagonists in the vlPAG blocked OFQ/N 1–17 -induced analgesia on the tail-flick test elicited from the amygdala, and whether pretreatment of general and selective opioid antagonists in the amygdala blocked OFQ/N 1–17 -induced analgesia elicited from the vlPAG of rats. OFQ/N 1–17 -induced analgesia elicited from the amygdala was significantly and markedly reduced following vlPAG pretreatment with a dose range of either naltrexone, β-funaltrexamine (β-FNA, μ), nor-binaltorphamine (NBNI, κ) or naltrindole (NTI, δ). In contrast, opioid antagonists administered into misplaced mesencephalic control placements ventral and lateral to the vlPAG actually enhanced OFQ/N 1–17 -induced analgesia elicited from the amygdala. OFQ/N 1–17 -induced analgesia elicited from the vlPAG was significantly and markedly reduced following amygdala pretreatment with naltrexone and NBNI, to a lesser degree by NTI, and was unaffected by β-FNA. Yet, opioid antagonists administered into misplaced amygdala control placements were generally ineffective in altering OFQ/N 1–17 -induced analgesia elicited from the vlPAG. Latencies were transiently increased by general, but not selective opioid antagonist treatment alone in the amygdala, but not the vlPAG. These data indicate reciprocal and regional interactions between the amygdala and vlPAG in the mediation of OFQ/N 1–17 by classic opioid receptor subtype antagonists in rats.
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reversal of sex differences in morphine analgesia elicited from the Ventrolateral Periaqueductal Gray in rats by neonatal hormone manipulations
Brain Research, 2002Co-Authors: Eliza K. Krzanowska, Sonoko Ogawa, Donald W Pfaff, Richard J. BodnarAbstract:Abstract Male rats display significantly greater analgesic responses than female rats following systemic, ventricular and intracerebral morphine administration into either the Ventrolateral Periaqueductal Gray (vlPAG) or the rostral ventromedial medulla, and following beta-endorphin administration into the vlPAG. Although adult gonadectomy severely reduces nonopioid forms of swim stress-induced analgesia, the marked sex differences in morphine analgesia were minimally affected by either male or female adult gonadectomy. Since very little is known about neonatal effects of gonadal hormones upon sex differences in morphine analgesia elicited from the vlPAG, the present study evaluated the effects of neonatal (within 1 day of birth) castration in male rat pups relative to sham-operated controls, and systemic androgenization with testosterone propionate in female rat pups relative to vehicle-injected controls upon baseline nociceptive thresholds and morphine analgesia elicited from the vlPAG in rats tested as adults. Significant sex differences in morphine analgesia elicited from the vlPAG were observed with adult males receiving neonatal sham surgeries displaying significantly greater morphine analgesia on two nociceptive measures than adult females tested during the estrous phase and receiving neonatal vehicle injections. Neonatal gonadectomy essentially reversed the pattern of sex difference effects upon morphine analgesia elicited from the vlPAG. Neonatally-castrated male rats tested in adulthood displayed dramatic reductions in morphine analgesia elicited from the vlPAG on both the tail-flick (∼15-fold rightward shift) and jump (6-fold rightward shift) tests relative to sham-operated males, and essentially mirrored those of vehicle-treated females. Conversely, neonatally-androgenized female rats tested in adulthood displayed dramatic increases in morphine analgesia elicited from the vlPAG on the tail-flick (5-fold leftward shift) and jump (12-fold leftward shift) tests relative to vehicle-treated females, and approximated those observed in sham-operated males. The potent differences between neonatally-castrated and sham-operated male rats and between neonatally-androgenized and vehicle-treated female rats suggest a possible ‘organizational’ role of gonadal hormones in mediating sex differences in morphine analgesia elicited from the vlPAG.
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analysis of sex and gonadectomy differences in β endorphin antinociception elicited from the Ventrolateral Periaqueductal Gray in rats
European Journal of Pharmacology, 2000Co-Authors: Eliza K. Krzanowska, Richard J. BodnarAbstract:Abstract Male rats exhibit significantly greater antinociception following central administration of morphine than female rats. The present study examined potential differences in β-endorphin (5.2–26 μg) antinociception elicited from the Ventrolateral Periaqueductal Gray in adult sham-operated and gonadectomized male and female rats. Male rats displayed significantly greater peak (30 min) tail-flick latencies across the entire range of β-endorphin doses administered into the Ventrolateral Periaqueductal Gray than female rats tested during the estrous phase of the estrous cycle. Adult gonadectomy failed to appreciably change the pattern of this effect in either males of females. Thus, antinociception elicited from the Ventrolateral Periaqueductal Gray by β-endorphin, like morphine, is sensitive to sex differences.
Daoshu Luo - One of the best experts on this subject based on the ideXlab platform.
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involvement of the Ventrolateral Periaqueductal Gray matter central medial thalamic nucleus basolateral amygdala pathway in neuropathic pain regulation of rats
Frontiers in Neuroanatomy, 2020Co-Authors: Yi Sun, Jing Wang, Shaohua Liang, Yanbing Chen, Daoshu LuoAbstract:The central medial nucleus (CM), a prominent cell group of the intralaminar nuclei (ILN) of the thalamus, and the Ventrolateral Periaqueductal Gray matter (vlPAG) are two major components of the medial pain system. Whether vlPAG and CM are input sources of nociceptive information to the basolateral amygdala (BLA) and whether they are involved in neuropathic pain regulation remain unclear. Clarifying the hierarchical organization of these subcortical nuclei (vlPAG, CM, and BLA) can enhance our understanding on the neural circuits for pain regulation. Behavioral test results showed that a CM lesion made by kainic acid (KA) injection could effectively alleviate mechanical hyperalgesia 4, 6, and 8 days after spared nerve injury (SNI) surgery, with the symptoms returning after 10 days. Morphological studies revealed that: (1) the CM received afferents from vlPAG and sent efferents to BLA, indicating that an indirect vlPAG-CM-BLA pathway exists; (2) such CM-BLA projections were primarily excitatory glutamatergic neurons as revealed by fluorescence in situ hybridization; (3) the fibers originated from the CM-formed close contacts with both excitatory and inhibitory neurons in the BLA; and (4) BLA-projecting CM neurons expressed Fos induced by SNI and formed close contacts with fibers from vlPAG, suggesting that the vlPAG-CM-BLA indirect pathway was activated in neuropathic pain conditions. Finally, the vlPAG-CM-BLA indirect pathway was further confirmed using anterograde and monosynaptic virus tracing investigation. In summary, our present results provide behavioral and morphological evidence that the indirect vlPAG-CM-BLA pathway might be a novel pain pathway involved in neuropathic pain regulation.
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involvement of the Ventrolateral Periaqueductal Gray matter central medial thalamic nucleus basolateral amygdala pathway in neuropathic pain regulation of rats
Frontiers in Neuroanatomy, 2020Co-Authors: Yi Sun, Jing Wang, Shaohua Liang, Yanbing Chen, Daoshu LuoAbstract:The central medial nucleus (CM), a prominent cell group of the intralaminar nuclei of the thalamus and the Ventrolateral Periaqueductal Gray matter (vlPAG), are two major components of the medial pain system. Whether the vlPAG and CM are input sources of nociceptive information to the basolateral amygdala (BLA) and whether they are involved in neuropathic pain regulation remains unclear. Clarifying the hierarchical organization of these subcortical nuclei (vlPAG, CM and BLA) can enhance our understanding on the neural circuits for pain regulation. Behavioral tests showed that CM lesion made by kainic acid (KA) injection could effectively alleviate mechanical hyperalgesia in 4, 6, and 8 d after spared nerve injury (SNI) surgery, with the symptoms returning back after 10 d. Morphological studies revealed that: (1) the CM received afferents from the vlPAG and sent efferents to the BLA, indicating that there exists an indirect vlPAG-CM-BLA pathway; (2) such CM-BLA projections were primarily excitatory glutaminergic neurons as revealed by fluorescence in situ hybridization; (3) the fibers originated from the CM formed close contacts with both excitatory and inhibitory neurons in the BLA; (4) BLA projecting CM neurons expressed Fos induced by SNI and formed close contacts with fibers form vlPAG, suggesting the vlPAG-CM-BLA indirect pathway was activated in neuropathic pain conditions. Finally, the vlPAG-CM-BLA indirect pathway was further confirmed by using anterograde and monosynaptic virus tracing investigation. In summary, our present results provide behavioral and morphological evidences for that the indirect vlPAG-CM-BLA pathway might be a novel pain pathway involved in neuropathic pain regulation.
William R. Millington - One of the best experts on this subject based on the ideXlab platform.
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the initial fall in arterial pressure evoked by endotoxin is mediated by the Ventrolateral Periaqueductal Gray
Clinical and Experimental Pharmacology and Physiology, 2016Co-Authors: William R. Millington, Sertac M Yilmaz, Carlos FelederAbstract:This study tested the hypothesis that the initial fall in arterial pressure evoked by lipopolysaccharide (LPS) is mediated by the Ventrolateral column of the midbrain Periaqueductal Gray region (vlPAG). To test this hypothesis, the local anaesthetic lidocaine (2%; 0.1 μL, 0.2 μL or 1.0 μL), the delta opioid receptor antagonist naltrindole (2 nmol) or saline was microinjected into the vlPAG of isoflurane-anaesthetized rats bilaterally and LPS (1 mg/kg) or saline was administered intravenously 2 min later. Both lidocaine and naltrindole inhibited LPS-evoked hypotension significantly but did not affect arterial pressure in saline-treated control animals. Neither lidocaine nor naltrindole altered heart rate significantly in either LPS-treated or control animals. Microinjection of lidocaine or naltrindole into the dorsolateral PAG was ineffective. These data indicate that the vlPAG plays an important role in the initiation of endotoxic hypotension and further show that delta opioid receptors in the vlPAG participate in the response.
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activation of mu opioid receptors in the Ventrolateral Periaqueductal Gray inhibits reflex micturition in anesthetized rats
Neuroscience Letters, 2004Co-Authors: Mark C Levendusky, Seiji Matsumoto, Penelope A Longhurst, Robert M Levin, William R. MillingtonAbstract:This study tested the hypothesis that morphine and other opiates cause urinary retention by activating mu opioid receptors in the midbrain Periaqueductal Gray (PAG) region. Selective mu, delta and kappa receptor agonists were microinjected into the PAG of urethane-anesthetized rats and the amplitude and incidence of bladder contractions were recorded during continuous saline infusion. Arterial pressure was monitored through a femoral artery catheter. Microinjection of the mu receptor agonist DAMGO into the Ventrolateral PAG (vlPAG) suppressed volume-evoked bladder contractions completely. Bladder contractions ceased within 5 min of DAMGO injection and remained essentially undetectable for the rest of the 20 min recording period. Microinjection of the delta receptor agonist DPDPE into the vlPAG did not significantly affect either the amplitude of bladder contractions or the time interval separating contractions. The kappa receptor agonist U-69593 caused no discernible change in amplitude but increased the interval between bladder contractions significantly. Microinjection of DAMGO, DPDPE or U-69593 into the lateral or dorsolateral PAG columns was ineffective. DAMGO injection into the vlPAG increased arterial pressure whereas DPDPE and U-69593 produced a small but significant depressor response. These data support the hypothesis that mu and kappa receptors in the vlPAG participate in the micturition reflex.
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evidence that hemorrhagic hypotension is mediated by the Ventrolateral Periaqueductal Gray region
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2001Co-Authors: Sinan Cavun, William R. MillingtonAbstract:Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. This study tested the hypothesis that the decompensatory phase of hemorrhage is mediated by the Ventrolateral periaqu...
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blockade of delta opioid receptors in the Ventrolateral Periaqueductal Gray region inhibits the fall in arterial pressure evoked by hemorrhage
Journal of Pharmacology and Experimental Therapeutics, 2001Co-Authors: Sinan Cavun, Garth E. Resch, Adam D. Evec, Michelle M Rapaconbaker, William R. MillingtonAbstract:Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. The central mechanism that initially triggers the fall in arterial pressure evoked by hemorrhage is not well understood, although opioid neurons are thought to play a role. This study tested the hypothesis that hemorrhagic hypotension is mediated by delta opioid receptors in the Ventrolateral Periaqueductal Gray (vlPAG), a region importantly involved in opioid analgesia. Depressor sites were first identified by microinjecting dl-homocysteic acid (20 nmol/0.1 μl) or β-endorphin (0.5 nmol/0.1 μl) into the vlPAG of halothane-anesthetized rats. Consistent with earlier reports,dl-homocysteic acid injection into the caudal vlPAG lowered arterial pressure and heart rate; β-endorphin evoked a comparable depressor response, but did not affect heart rate. Naloxone or selective opioid receptor antagonists were subsequently injected into the vlPAG 5 min before hemorrhage (1.9 or 2.5 ml/100 g of body weight over 20 min) was initiated using the same stereotaxic coordinates. Naloxone injection into the caudal vlPAG completely prevented the fall in arterial pressure evoked by hemorrhage. The response was dose-dependent and evident with both fixed volume and fixed pressure hemorrhage. The delta opioid receptor antagonist naltrindole inhibited hemorrhagic hypotension significantly in both conscious and anesthetized rats but mu and kappa receptor antagonists were ineffective. β-Endorphin1–27, an endogenous opioid receptor antagonist, was also significantly inhibitory. Naltrindole was ineffective when injected into the dorsolateral Periaqueductal Gray and did not influence cardiovascular function in nonhemorrhaged animals. These data support the hypothesis that hemorrhagic hypotension is mediated by delta opioid receptors in the vlPAG.
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Delta opioid receptors in the Ventrolateral Periaqueductal Gray region mediate hemorrhagic hypotension (Abstract
2000Co-Authors: Sinan Cavun, Garth E. Resch, Adam D. Evec, Michelle M. Rapacon-baker, William R. MillingtonAbstract:Severe hemorrhage lowers arterial pressure by suppressing sympathetic activity. The central mechanism that initially trig-gers the fall in arterial pressure evoked by hemorrhage is not well understood, although opioid neurons are thought to play a role. This study tested the hypothesis that hemorrhagic hypo-tension is mediated by delta opioid receptors in the ventrolat-eral Periaqueductal Gray (vlPAG), a region importantly involved in opioid analgesia. Depressor sites were first identified by microinjecting DL-homocysteic acid (20 nmol/0.1 ml) or b-en-dorphin (0.5 nmol/0.1 ml) into the vlPAG of halothane-anesthe-tized rats. Consistent with earlier reports, DL-homocysteic acid injection into the caudal vlPAG lowered arterial pressure and heart rate; b-endorphin evoked a comparable depressor re-sponse, but did not affect heart rate. Naloxone or selectiv
