Direct Effects of α1-and α2-AdrenergicAgonists on Spinal and Cerebral Pial Vessels in Dogs

Iida, Hiroki; Ohata, Hiroto; Iida, Mami; Watanabe, Yukinaga; Dohi, Shuji

doi:10.1097/00000542-199908000-00023

Cited by 46 publications

(37 citation statements)

References 28 publications

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“…Opioid-adrenergic synergy could arise from pharmacokinetic interactions. In addition to their antinociceptive effects, a 2 AR agonists such as clonidine have a local vasoconstrictive effect (Asada and Lee, 1992;Iida et al, 1999) that can reduce drug clearance from the site of injection. Clonidine could therefore enhance the effect of another drug by maintaining it at a high local drug concentration.…”

Section: Discussionmentioning

confidence: 99%

The Delta-Opioid Receptor Is Sufficient, but Not Necessary, for Spinal Opioid-Adrenergic Analgesic Synergy

Chabot-Doré

Millecamps

Stone

2013

J Pharmacol Exp Ther

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Spinal administration of opioid and a 2 -adrenergic receptor (a 2 AR) agonists produces analgesia, and agonists interact synergistically when coadministered. The molecular mechanism underlying this synergy is largely unknown. Pharmacological studies have identified both the delta and the mu-opioid receptors (DOR and MOR) as candidate receptors capable of interacting synergistically with a 2 AR agonists. However, recent studies attribute the antinociceptive effect of DOR agonists to actions at the MOR, calling the role of DOR in opioid-adrenergic synergy into question. Other studies suggesting that DOR is implicated in morphine antinociception raise the possibility that DOR is nonetheless required for morphine synergy with a 2 AR agonists. This study aimed to determine whether DOR activation is sufficient and necessary to mediate opioid-adrenergic synergistic interactions in the spinal cord. The antinociceptive effects of clonidine, [D-Ala 2 ]-deltorphin II (DeltII), morphine, and [D-Ala 2 , N-Me-Phe 4 , Gly-ol 5 ]-enkephalin (DAMGO) were evaluated using the substance P (SP) behavioral assay in wild type (WT) and DOR-knockout (KO) mice. Opioid-adrenergic drug interactions were evaluated after spinal coadministration of clonidine with DeltII, morphine, or DAMGO. Isobolographic analyses of dose-response curves determined whether interactions were synergistic or additive. The absence of DeltII antinociceptive efficacy in DOR-KO confirmed its selectivity in the SP assay. Although DeltII1clonidine interacted synergistically in WT mice, no interaction with clonidine was observed in DOR-KO mice. Clonidine was synergistic with morphine in both mouse strains. DAMGO did not synergize with clonidine in either strain. These findings confirm that although other opioid receptors can interact synergistically with a 2 AR agonists, DOR is sufficient for spinal opioid-adrenergic interactions.

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Section: Discussionmentioning

confidence: 99%

The Delta-Opioid Receptor Is Sufficient, but Not Necessary, for Spinal Opioid-Adrenergic Analgesic Synergy

Chabot-Doré

Millecamps

Stone

2013

J Pharmacol Exp Ther

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“…However, they did not evaluate the possible toxic effects of dexmedetomidine on cerebral neuronal cells when it was administered by epidural route. Iida et al reported that cerebral vessels were more sensitive to the α₂-adrenergic stimulation than the spinal counterparts (10). Hence, we thought that the toxic effect of centrally administered dexmedetomidine into the cerebrospinal fluid by intracisternal route on cerebral neurons might be resulted from a direct vasoconstrictive effect mediated by cerebral vascular α₂-adrenergic receptors.…”

Section: Kose Ea Et Al: Effects Of Intracisternal Dexmedetomidine Onmentioning

confidence: 79%

“…On the other hand, it has been shown by Konakci et al. that dexmedetomidine produced moderate or severe demyelinization of myelin sheats in the white matter of spinal cord in rabbit, when it is administered by the epidural route (14), and this effect has been explained by the agent's vasoconstrictive effect on medullar spinal vessels (10). It is known that topical application of dexmedetomidine had vasoconstrictor effects both on cerebral pial arterial and venous vessels (11).…”

Section: Introductionmentioning

confidence: 99%

Effects of intracisternal dexmedetomidine on cerebral neuronal cells in rat: a preliminary study

Kose¹,

Bakar²,

Kasımcan³

et al. 2012

Turkish Neurosurgery

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AIm:The aim was to investigate whether dexmedetomidine had a toxic effect on cerebral neurons when it was administered centrally into the cerebrospinal fluid by the intracisternal route. mAterIAl and methOds: Eighteen rats were anesthetized and the right femoral artery was cannulated. Mean arterial pressures, heart rates, arterial carbon dioxide tension, arterial oxygen tension, and blood pH were recorded. When the free cerebrospinal fluid flow was seen, 0.1 ml normal saline (Group SIC, n=6) or 9 µg/kg diluted dexmedetomidine in 0.1 ml volume (Group DIC, n=6) was administered into the cisterna magna of rats. After 24 hours, the whole body blood was collected for measurement of plasma lipid peroxidation (LPO) levels. The hippocampal formations used for histopathological examination and measurement of tissue LPO levels.results: There was a statistically significant difference between the DIC/SIC groups and DIC/CONTROL groups regarding the brain LPO levels (p=0.002, p<0.001, respectively). Plasma LPO levels were statistically different between the CONTROL/DIC groups, CONTROL/SIC groups, DIC/ SIC groups (p=0.002, p=0.047, p=0.025, respectively), The picnotic neuron counts were different between the CONTROL/SIC groups, CONTROL/ DIC groups, DIC/SIC groups (p<0.001, p=0.001, p=0.024, respectively). COnClusIOn:In conclusion, dexmedetomidine had a toxic effect on cerebral neurons when it was administered centrally into the cerebrospinal fluid by the intracisternal route.KeywOrds: Dexmedetomidine, Intracisternal, Intrathecal, Hippocampus, Brain, Cerebral neuron ÖZ AmAÇ: İntrasisternal olarak serebrospinal sıvı içine santral yolla verilen deksmedetomidinin serebral nöronlar üzerinde toksik etkisinin olup olmadığını araştırmak amaçlandı. yÖntem ve GereÇler: On sekiz sıçana anestezi verildikten sonra sağ femoral arterleri kanülize edildi. Ortalama arter basınçları, kalp hızları, arteriyal karbon dioksit basınçları, arteriyal oksijen basınçları, kan pH değerleri kaydedildi. Serbest serebrospinal sıvı akışı görüldükten sonra ratların sisterna magnaları içine 0,1 ml serum fizyolojik (Grup SIC, n=6) veya 0,1 ml volüm içinde 9 µg/kg sulandırılmış deksmedetomidin (Grup DIC, n=6) verildi. Yirmi dört saat sonra lipid peroksidasyon (LPO) seviyesi ölçümleri için tüm vücut kanı toplandı. Histopatolojik inceleme ve doku LPO seviyesi ölçümleri için hipokampüs kullanıldı.BulGulAr: Beyin dokusu LPO seviyeleri yönünden DIC/SIC ve DIC/CONTROL grupları arasında istatistiksel belirgin farklılık vardı (sırasıyla, p=0.002, p<0.001). Plazma LPO seviyeleri CONTROL/DIC, CONTROL/SIC, DIC/SIC grupları arasında istatistiksel olarak farklıydı (sırasıyla, p=0,002, p=0,047, p=0,025). Piknotik nöron sayıları CONTROL/SIC, CONTROL/ DIC, DIC/SIC grupları arasında istatiksel olarak farklıydı (sırasıyla, p<0,001, p=0,001, p=0,024). sOnuÇ: Sonuç olarak, intrasisternal olarak serebrospinal sıvı içine santral yolla verilen deksmedetomidinin serebral nöronlar üzerine toksik etkisi olduğu görüldü.

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“…2). In addition, spinal arterioles seemed to be more sensitive to alpha-1-adrenergic stimulation than to alpha-2-adrenergic stimulation, whereas for cerebral arterioles, the reverse was true (i.e., more sensitive to alpha-2-adrenergic stimulation than to alpha-1-adrenergic stimulation) [4].…”

Section: Response Characteristics Of Spinal Vesselsmentioning

confidence: 89%

Anesthesia and cerebrospinal microcirculation: assessment using cranial- and spinal-window techniques

Iida

Takenaka

2011

J Anesth

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A good understanding of the characteristics of cerebrospinal-vessel reactivity is advantageous if an appropriate circulation is to be maintained within the central nervous system (CNS) during surgery. In addition, it is useful to know that ischemia-reperfusion, disruption of the bloodbrain (spinal cord)-barrier (BBB), and hypothermia could all potentially modulate the effects on cerebrospinal circulation and cerebrospinal-vessel reactivity induced by any vasoactive drugs administered during anesthesia. We therefore focused on, and present here, the significance of changes in cerebrospinal microcirculation that occur in relation to the perioperative period. Our studies entailed an assessment of the relevant parameters by means of the cranial-and spinal-window techniques in animals in vivo. It is generally agreed that such techniques facilitate in vivo observations of pial vessels. We originated the spinalwindow technique presented here, although it is closely based on the cranial-window technique (Fig. 1). Measurement of pial-vessel diameter provides direct information about the effects of test drugs and physiological changes on cranial and spinal vessels. However, such information is obtainable only from the superficial vessels and does not provide a direct measurement of cerebral or spinal cord blood flow (SCBF), unlike the use of microspheres, hydrogen clearance, or laser Doppler flowmetry.

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Direct Effects of α1-and α2-AdrenergicAgonists on Spinal and Cerebral Pial Vessels in Dogs

Abstract: Dexmedetomidine and clonidine constricted spinal vessels in a concentration-dependent manner, but such vasoconstrictions were smaller than those induced by phenylephrine and epinephrine.

Cited by 46 publications

References 28 publications

The Delta-Opioid Receptor Is Sufficient, but Not Necessary, for Spinal Opioid-Adrenergic Analgesic Synergy

The Delta-Opioid Receptor Is Sufficient, but Not Necessary, for Spinal Opioid-Adrenergic Analgesic Synergy

Effects of intracisternal dexmedetomidine on cerebral neuronal cells in rat: a preliminary study

Anesthesia and cerebrospinal microcirculation: assessment using cranial- and spinal-window techniques

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