Salvinorin a Produces Cerebrovasodilation Through Activation of Nitric Oxide Synthase, ␬ Receptor, and Adenosine Triphosphate–Sensitive Potassium Channel

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Salvinorin A Produces Cerebrovasodilation through Activation of Nitric Oxide Synthase, ␬ Receptor, and Adenosine Triphosphate–sensitive Potassium Channel

Diansan Su, M.D., Ph.D.,* John Riley, B.A.,† Willis J. Kiessling, B.A.,† William M. Armstead, Ph.D.,‡ Renyu Liu, M.D., Ph.D.§

ABSTRACT Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/114/2/374/253404/0000542-201102000-00025.pdf by guest on 02 October 2021 What We Already Know about This Topic • Salvinorin A is a nonopioid selective ␬ opioid receptor agonist. Background: Salvinorin A is a nonopioid, selective ␬ opioid– receptor agonist. Despite its high potential for clinical applica- tion, its pharmacologic profile is not well known. In the current study, we hypothesized that salvinorin A dilates pial arteries via What This Article Tells Us That Is New activation of nitric oxide synthase, adenosine triphosphate–sen- • Salvinorin A is an efficacious cerebral vascular dilator in the sitive potassium channels, and opioid receptors. newborn piglet, under normal conditions and with constriction from endothelin and hypocarbia. Methods: Cerebral artery diameters and cyclic guanosine • Salvinorin A acts via the ␬ opioid receptor, nitric oxide gener- monophosphate in cortical periarachnoid cerebrospinal fluid ation, and adenosine triphosphate–sensitive potassium chan- were monitored in piglets equipped with closed cranial win- nel to produce cerebral vasodilatation. dows. Observation took place before and after salvinorin A administration in the presence or absence of an opioid antagonist (naloxone), a ␬ opioid receptor–selective antagonist istration every 2 min. Vasodilatation and the associated cy- (norbinaltorphimine), nitric oxide synthase inhibitors clic guanosine monophosphate elevation in cerebrospinal (N(G)-nitro-L-arginine and 7-nitroindazole), a dopamine fluid were abolished by preadministration N(G)-nitro-L-arginine, but not 7-nitroindazole. Although naloxone, norbin- receptor D2 antagonist (sulpiride), and adenosine triphos- ϩ phate–sensitive potassium and Ca2 -activated K channel an- altorphimine, and glibenclamide abolished salvinorin A–in- tagonists (glibenclamide and iberiotoxin). The effects of duced cerebrovasodilation, this response was unchanged by salvinorin A on the constricted cerebral artery induced by iberiotoxin and sulpiride. Hypocarbia and endothelin-con- hypocarbia and endothelin were investigated. Data were an- stricted pial arteries responded similarly to salvinorin A, to alyzed by repeated measures ANOVA (n ϭ 5) with statistical the extent observed under resting tone. significance set at a P value of less than 0.05. Conclusions: Salvinorin A dilates cerebral arteries via acti- Results: Salvinorin A induced immediate but brief vasodi- vation of nitric oxide synthase, adenosine triphosphate–sen- ␬ latation that was sustained for 30 min via continual admin- sitive potassium channel, and the opioid receptor.

* Visiting Scholar from Department of Anesthesiology, Renji ALVINORIN A is an active component of Salvia divino- Hospital, Shanghai Jiaotong University, School of Medicine, Shang- rum, a perennial herb of the Lamiaceae (mint) family, in- hai, China, and Assistant Professor, † Research Assistant, ‡ Professor, S § Assistant Professor, Department of Anesthesiology and Critical digenous to Mexico. Salvia divinorum has long been tradition- Care, Hospital of University of Pennsylvania, Philadelphia, ally used by local people to produce hallucinogenic experiences Pennsylvania. essential for spiritual divination.1,2 Salvinorin A is a highly effi- Received from the Department of Anesthesiology and Critical cacious, naturally occurring nonpeptide, and it is the only Care, Hospital of University of Pennsylvania, Philadelphia, Pennsyl- ␬ 1,3 vania. Submitted for publication May 20, 2010. Accepted for publi- known nonnitrogenous opioid receptor (KOR) agonist. cation October 12, 2010. Support was provided from institutional Similar to the history of opium, Salvia divinorum is a and/or departmental sources as well as the Foundation for Anes- naturally abundant plant that has been used by human be- thesia Education and Research (Rochester, Minnesota) Grant no. MRTG-02/15/2008, and the National Institutes of Health (Bethesda, ings for recreational purposes for several centuries. Salvinorin Maryland) Grant no. HD57355. A has been proposed as a new opioid receptor agonist for Address correspondence to Dr. Liu: Department of Anesthesiol- clinical use.4–6 However, none of KOR agonists have been ogy and Critical Care, University of Pennsylvania School of Medi- used clinically because of their known adverse effects. Al- cine, 336 John Morgan Building, 3620 Hamilton Walk, Philadelphia, Pennsylvania 19104. [email protected]. Information on pur- though Salvinorin A does not belong to the opioid drug class, chasing reprints may be found at www.anesthesiology.org or on the despite its KOR-agonist properties, it is banned in many masthead page at the beginning of this issue. ANESTHESIOLOGY’s counties and much of the United States. articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue. Unlike the KOR agonists, salvinorin A does not produce 2 Copyright © 2011, the American Society of Anesthesiologists, Inc. Lippincott frank hallucinatory effects, and has no dysphoric actions. Williams & Wilkins. Anesthesiology 2011; 114: 374–9 Many intrinsic characters of the compound (e.g., quick on-

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set, short-acting sedative effect, no respiratory depression)7–9 mmHg. Artificial CSF was warmed to 37–38°C before applica- make it attractive for use in well-controlled perioperative tion to the cerebral cortical surface. Pial arteries were observed settings. Therefore, its physiologic profile and related mech- with a television camera mounted on a dissecting microscope. anism should be well investigated—especially its effects on Vascular diameter was measured from a video monitor that the central nervous system, including cerebral vasculature in connected the camera with a video microscaler (FOR-A, IV550, normal and pathologic conditions. Although some neuro- Tokyo, Japan). logic effects of salvinorin has been well documented,1,10,11 no data exist for the cerebral vasculature effect of salvinorin A. Experimental Protocols We have demonstrated that other KOR agonists Pial artery diameter (small artery, 120–160 ␮m; arteriole, (dynorphin and U50488) can dilate the pial artery 10,12 50–70 ␮m) was monitored and recorded every half minute through the nitric oxide pathway. In the current Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/114/2/374/253404/0000542-201102000-00025.pdf by guest on 02 October 2021 for 10 min after injection of artificial CSF in the presence or study, we hypothesized that salvinorin A might dilate pial arteries under resting and increased tone conditions in- absence of the investigated drug. In general, the window was duced by hypocarbia or endothelin via activation of nitric flushed in 30 s with 1–2 ml CSF through the port connected oxide synthase, adenosine triphosphate–sensitive potas- into the side of the window. CSF samples were collected for sium (K ) channels, and ␬ receptors. cGMP analysis before medication administration and 10 ATP min afterward. We collected the cerebral cortical periarach- Materials and Methods noid CSF by slowly infusing CSF into one port of the window and allowing the CSF to drip freely into a collection Ն Salvinorin A (purity 98%), sodium nitroprusside (SNP), tube on the opposite port. N(G)-nitro-L-arginine (L-NNA), glibenclamide, iberiotoxin, Responses to salvinorin A (10 nM and 1 ␮M, dissolved cromakalim, calcitonin gene–related polypeptide, NS1619, nal- with alcohol) and SNP (10 nM and 1 ␮M), were obtained in oxone, methionine enkephalin, norbinaltorphimine, 7-nitroi- the absence and presence of L-NNA (1 ␮M), a nitric oxide ndazole, sulpiride, and isoproterenol are obtained from Sigma- synthase (NOS) inhibitor, and 7-nitroindazole (100 nM), an Aldrich (St. Louis, MO). All other chemicals were also obtained antagonist of neuronal NOS (nNOS). from Sigma-Aldrich and were of reagent grade. To distinguish the direct versus permissive role of nitric oxide in the salvinorin A–induced dilation response, pial Animals and Surgery artery diameter changes were recorded after SNP (100 pM), Newborn pigs (aged up to 6 days, 1.3–1.8 kg) of both gen- a subthreshold vascular concentration of a nitric oxide do- ders were used for this study. Protocols were approved by the nor, as well as after L-NNA and salvinorin A coadministra- Institutional Animal Care and Use Committee of the Uni- tion. Also determined were the influences of the following on versity of Pennsylvania (Philadelphia, Pennsylvania). Ani- pial artery response: sulpiride (100 nM), a dopamine recep- mals were induced with isoflurane (1–2 minimum alveolar tor D2 antagonist; glibenclamide (100 nM), a KATP channel ␣ ϩ ϩ concentration) and maintained with -chloralose (80–100 antagonist; iberiotoxin (100 nM), a Ca2 -activated K ⅐ ⅐ mg/kg supplemented with 5 mg kg h IV). Both femoral channel antagonist; cromakalim (1 ␮M); calcitonin gene– arteries were catheterized to monitor blood pressure and ␮ related polypeptide (10 nM and 1 M),aKATP agonist; and ϩ ϩ blood gas. A catheter was inserted into the right femoral vein NS1619 (10 nM and 1 ␮M),aCa2 -activated K channel for medication administration. Animals were ventilated with agonist. Finally, the effects of the following were investi- room air after tracheal cannulation. Rectal temperature was gated: naloxone (1 mg/kg IV) and topical norbinaltorphi- maintained at 37–39°C by a heating pad. A closed cranial win- ␮ 12 mine (1 M), KOR antagonists; and methionine enkephalin dow was placed, as previously described, for direct pial artery and isoproterenol (10 nM and 1 ␮M each), the latter being a visualization and diameter measurement. The closed cranial ␤-adrenergic receptor agonist. All tested drug solutions were window consisted of three parts: a stainless steel ring, a circular made fresh on the day of use. Pial artery response to contin- glass cover slip, and three ports consisting of 17-gauge hypoder- ual administration of salvinorin A every 2 min, was recorded mic needles attached to three precut holes in the stainless steel for 30 min to determine whether sustained vascular dilata- ring. Cortical periarachnoid cerebrospinal fluid (CSF) was col- tion could be achieved. lected through the cranial window port for cyclic guanosine monophosphate (cGMP) determination. Before placing the window, the scalp was reflected and an opening was made in the cGMP Determination skull over the parietal cortex. Then the dura mater was cut and To determine the role of the nitric oxide pathway in the ob- retracted over the bone edge. The cranial window was placed on served effects of salvinorin on cerebral vasculature, CSF samples the cranial opening and cemented in place with dental acrylic. were collected for cGMP determination before and after salvi- The space under the window was filled with artificial CSF with norin A administration with or without L-NNA and norbinal- the following composition (in mM): 3.0 KCl; 1.5 MgCl2; 1.5 torphimine pretreatment. Commercially available ELISA kits calcium chloride; 132 NaCl; 6.6 urea; 3.7 dextrose; 24.6 (Enzo Life Sciences International, Inc., Plymouth Meeting, PA)

NaHCO3 per liter; pH 7.33; PCO2, 46 mmHg; and PO2 43 were used to quantify cGMP concentrations.

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Fig. 1. In the newborn piglet, salvinorin A dilated the brain pial artery in a dose-dependent manner (n ϭ 5). (A) N(G)-nitro-L- arginine (L-NNA), a nitric oxide synthase inhibitor, blocks the dilation effects of salvinorin A, but not sodium nitroprusside (SNP). (B) Continual administration every 2 min of salvinorin A can sustain dilation of the pial artery for 30 min. (C) The neuronal NOS inhibitor 7-nitroindazole (7-NINA) did not block the dilation effects of salvinorin A. (D) Although 100-pM SNP restored the construction effects of L-NNA, it did not restore the dilation effects induced by salvinorin A, which was blocked by L-NNA.

Salvinorin A on Constricted Vessels This response was abolished by L-NNA, the NOS inhibitor, but To test the cerebrovascular effect of salvinorin during in- not by 7-nitroindazole, the nNOS antagonist (figs. 1A and C). creased cerebrovascular tone, we induced vasoconstriction The dilation response to SNP was not affected by L-NNA. via hypocarbia (PaCO2 reduced 20–30% for 10 min) and Likewise, 100-pM SNP had no effects on the pial artery, but it endothelin (0.1 pM). Pial artery diameter was monitored at restored the constriction induced by L-NNA although it did not baseline, after hypocarbia (n ϭ 4) or endothelin (n ϭ 5), and restore the dilation response of salvinorin A as blocked by L- after administration of salvinorin A (10 nM and 1 ␮M). NNA (fig. 1D). Dilation in response to salvinorin A was associated with increased cGMP in CSF; L-NNA blocked cGMP Statistical Analysis elevation (fig. 2). No significant blood pressure changes oc- All data (diameters and cGMP) were analyzed using curred during salvinorin administration. ANOVA with repeated measures (two-tailed) followed by Bonferroni post hoc test (SPSS 10.0 for Windows; Interna- KATP Channel Involves in the Dilatation Effect tional Business Machines Corporation, Armonk, NY). A P of Glibenclamide, the KATP channel inhibitor—but not iberio- 2ϩ ϩ less than 0.05 was considered statistically significant. Values toxin, the Ca -activated K channel inhibitor—blocked are represented as mean Ϯ SEM of the absolute value or as the dilation effects of salvinorin A. Combined glibenclamide percentage change from baseline values. Distributions of all and iberiotoxin in any sequence also blocked salvinorin values were evaluated by histogram. A–induced dilation (fig. 3). Glibenclamide, but not iberiotoxin, blocked dilation in response to both test doses of cromakalim and calcitonin gene–related polypeptide. Iberio- Results toxin, but not glibenclamide, blocked the dilation effects of Dilation Effect and the Role of Nitric Oxide Pathway NS1619 at both dosing levels (fig. 4). In a dose-dependent manner, salvinorin A dilated the pial artery (fig. 1A). This effect was observed immediately after Opioid Receptor Blocked Dilation Effect of Salvinorin salvinorin administration and lasted less than 5 min for both Norbinaltorphimine, the KOR-selective antagonist, and nalox- test doses. When salvinorin A was administered every 2 min, one blocked the dilation effects of salvinorin A and methionine sustained dilation effects were observed for 30 min (fig. 1B). enkephalin. This response was unaffected by isoproterenol (figs.

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constricted conditions as induced by endothelin and hypocarbia. Dilatation effects were observed immediately after salvinorin administration, lasted less than 5 min for each test dose (10 nM and 1 ␮M), and were dose dependent. Sus- tained dilation effects were observed for 30 min with continual administration every 2 min. The activation of the opioid

receptor, NOS, and KATP channel were involved in the signal pathway of dilation effects. We previously demonstrated that U50488, an exogenous KOR agonist, and dynorphin, an endogenous KOR agonist, dilate the pial artery.12 Pei et al.13 demonstrated that Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/114/2/374/253404/0000542-201102000-00025.pdf by guest on 02 October 2021 U50488 relaxes the isolated aortic artery in rat in a dose- dependent manner. Different from other KOR agonists, the Fig. 2. Salvinorin A increases cyclic guanosine monophos- dilatation effect of salvinorin is very short-lived, lasting less phate (cGMP) in the cerebrospinal fluid (CSF). N(G)-nitro-L- arginine (L-NNA) blocked salvinorin A –induced cGMP eleva- than 5 min. Therefore, salvinorin is the shortest acting ␬ tion and vascular dilation (n ϭ 5). agent known among the agonists—presenting research- ers with an opportunity to explore this novel agent that 5A and B). Likewise, sulpiride had no effect on the dilation would allow for easy management and titration in periop- 14 response of salvinorin A (fig. 5C). Norbinaltorphimine blocked erative and critical care settings. To achieve longer last- salvinorin A–induced cGMP elevation in the CSF. At both ing effects, infusion is the most common technique used dosing levels, there were no differences among cGMP concen- in clinical anesthesia. In the current study, we found that trations before versus after salvinorin A administration with nor- persistent vascular dilatation can be achieved for 30 min binaltorphimine pretreatment (P ϭ 1.0). via continual administration every 2 min. Because continual administration every 2 min results in a Salvinorin Dilates Pial Arteries in Increased sustained dilatory effects, the unique structure of salvinorin A, Cerebrovascular Tone Conditions not tachyphylaxis, contributes to its short-acting character. Ester Hypocarbia and endothelin significantly decreased the diam- linkage in its structure can be easily metabolized by esterase in eter of pial arteries (fig. 6). Salvinorin dilated pial arteries the blood and tissues. Tsujikawa et al.9 demonstrated that car- under increased tone conditions similar to that observed un- boxylesterase mainly involved in the salvinorin A hydrolysis in der normocapnic (resting tone) conditions. rat plasma and the degradation products including salvinorin B No significant differences between responses of the small which are not pharmacologically active. artery and arteriole were observed in any of above experi- Similar to other KOR agonists,12,13 the activation of ments. Thus, only changes in the small artery are presented. NOS, KATP channels, and opioid receptors mediated salvinorin A’s dilation effects. Goyagi et al.15 demonstrated that Discussion selective KOR agonist BRL 52537 protected the ischemic In the current study, we demonstrated that salvinorin A is a brain by attenuating nitric oxide production in the ischemic potent pial artery dilator in piglets under normal and vessel- striatum. Zeynalov et al.16 proved that the neuroprotection of BRL 52537 was lost in nNOS-null mice. Therefore, the KOR agonist BRL 52537 attenuated nNOS activity and ischemia-evoked nitric oxide production. However, in the current study, pial artery dilation to salvinorin A was abolished by the L-NNA, a nonspecific NOS inhibitor, but not 7-nitroindazole, a selective nNOS antagonist. This result in- dicates that nNOS is not involved in the dilative effective of salvinorin A. Because a subthreshold amount of the nitric oxide donor SNP failed to restore the dilation response, the elevation of cGMP in CSF is likely the result of stimulation, rather than inhibition, of nitric oxide production and direct activation of salvinorin on endothelial NOS rather than permissive enabling. The experimental paradigm used in this Fig. 3. Glibenclamide (Glib), but not iberiotoxin (Iberi), study does not allow us to determine the cellular site of blocked the dilation effects of salvinorin A (S). In any dosing sequence, combined glibenclamide and iberiotoxin blocked origin for the cGMP detected in CSF, but the origin may the dilation effects of salvinorin A (n ϭ 5). * First-administered include endothelial, vascular smooth muscle, and/or neu- agent. ronal cells.

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Fig. 4. Glibenclamide (Glib), but not iberiotoxin (Iberi), blocks the dilation effects of cromakalim and calcitonin gene–related polypeptide (CGRP). Iberiotoxin, but not glibenclamide, blocks the dilation effects of NS1619 (n ϭ 5). (A) Effects of 10 nM cromakalim, CGRP, and NS1619, in the presence versus absence of pretreatment agents. (B) Effects of 1 ␮M cromakalim, CGRP, and NS1619. * First-administered agent.

␬ KATP channel activation may result in hyperpolarization fects of salvinorin A, suggesting the important role of re- of the membrane of vascular smooth muscle cells. Membrane ceptor rather than the dopamine D2 receptor. potential changes would then regulate muscle relaxation The vascular dilative effect of salvinorin A observed in ϩ through alterations in Ca2 influx through voltage-depen- normal and constricted cerebral vessels by hypocarbia and ϩ dent Ca2 channels.17,18 To our knowledge, this is the first endothelin opens new possibilities for clinical applications.

study to demonstrate that salvinorin A actives the KATP Likely targets include treatment of cerebral vessel spasm in channel directly or indirectly. Different from many other clinical situations such as migraine and after subarachnoid

agents that can activate the KATP channel, salvinorin A can hemorrhage, where increase of endothelin plays an impor- 7,8 24 easily penetrate the blood-brain barrier. Because the KATP tant role. More studies are necessary to demonstrate the channel plays a crucial protective role against brain injury dilation effects of salvinorin A on other pathologic condi- from hypoxia, ischemia, and metabolic inhibition,19–22 tions. Similar to other short-acting agents, continuous infu- salvinorin A might be a potential neuroprotective agent for sion could be used to titrate and achieve sustained effects. future clinical use. In the current study, newborn piglets were used as study Although salvinorin A shows a high affinity for dopamine subjects. The piglet brain is gyrencephalic, similar in maturity to 23 D2 receptors, sulpiride, the dopamine D2 receptor selective human infant, and contains more white than grey matters, the antagonist, has no effects on the dilation effects of salvinorin former being selectively vulnerable to injury.25,26 The newborn A. On the contrary, naloxone and norbinaltorphimine, the piglet was also used because it is large enough for easy placement KOR-selective antagonist, abolished the vascular dilative ef- of a cranial window and vascular visualization. Cerebral vascular

Fig. 5. Naloxone and norbinaltorphimine, but not sulpiride, block the dilation effects of salvinorin A (n ϭ 5). (A) Naloxone and methionine enkephalin (Met-enk), but not isoprotenol, block the dilation effects of salvinorin A. (B) Norbinaltrophimine blocks the dilation effects of salvinorin A. (C) Sulpiride did not block the dilation effects of salvinorin A.

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9. Tsujikawa K, Kuwayama K, Miyaguchi H, Kanamori T, Iwata YT, Inoue H: In vitro stability and metabolism of salvinorin A in rat plasma. Xenobiotica 2009; 39:391–8 10. Nemeth CL, Paine TA, Rittiner JE, Be´guin C, Carroll FI, Roth BL, Cohen BM, Carlezon WA Jr: Role of kappa-opioid receptors in the effects of salvinorin A and ketamine on attention in rats. Psychopharmacology (Berl) 2010; 210:263–74 11. Grilli M, Neri E, Zappettini S, Massa F, Bisio A, Romussi G, Marchi M, Pittaluga A: Salvinorin A exerts opposite presyn- aptic controls on neurotransmitter exocytosis from mouse brain nerve terminals. Neuropharmacology 2009; 57:523–30 12. Devine JO, Armstead WM: The role of nitric oxide in opioid- induced pial artery vasodilation. Brain Res 1995; 675:257–63 13. Pei JM, Chen M, Wang YM, Wen J, Zhu YL: Kappa-opioid Downloaded from http://pubs.asahq.org/anesthesiology/article-pdf/114/2/374/253404/0000542-201102000-00025.pdf by guest on 02 October 2021 Fig. 6. In a dose-dependent manner, salvinorin A dilated the receptor stimulation contributes to aortic artery dilation constricted pial artery as induced by (A) hypocarbia (n ϭ 4) through activation of K(ATP) channel in the rats. Sheng Li and (B) endothelin (n ϭ 5). Xue Bao 2003; 55:91–5 14. Beers R, Camporesi E: Remifentanil update: Clinical science and utility. CNS Drugs 2004; 18:1085–104 responses in the newborn piglet are similar to those of human 15. Goyagi T, Toung TJ, Kirsch JR, Traystman RJ, Koehler RC, subjects in many clinical situations; no reports indicate a differ- Hurn PD, Bhardwaj A: Neuroprotective kappa-opioid recep- ence in responses. However, it is advisable to retain caution tor agonist BRL 52537 attenuates ischemia-evoked nitric ox- when interpreting these data for use in adult subjects. ide production in vivo in rats. Stroke 2003; 34:1533–8 16. 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