Psychoactive Plant Database - Neuroactive Phytochemical Collection

1. J Pharmacol Exp Ther. 2013 Dec;347(3):794-801. doi: 10.1124/jpet.113.207704. 
Epub 2013 Sep 19.

Spinal-supraspinal and intrinsic μ-opioid receptor agonist-norepinephrine 
reuptake inhibitor (MOR-NRI) synergy of tapentadol in diabetic heat hyperalgesia 
in mice.

Christoph T(1), Schröder W, Tallarida RJ, De Vry J, Tzschentke TM.

Author information:
(1)Department of Pain Pharmacology, Grünenthal GmbH, Aachen, Germany (T.C., 
W.S., J.D.V., T.M.T.); and Department of Pharmacology, Temple University School 
of Medicine and Centre for Substance Abuse Research, Philadelphia, Pennsylvania 
(R.J.T.).

Tapentadol is a μ-opioid receptor (MOR) agonist and norepinephrine reuptake 
inhibitor (NRI) with established efficacy in neuropathic pain in patients and 
intrinsic synergistic interaction of both mechanisms as demonstrated in rodents. 
In diabetic mice, we analyzed the central antihyperalgesic activity, the 
occurrence of site-site interaction, as well as the spinal contribution of 
opioid and noradrenergic mechanisms in a hotplate test. Tapentadol (0.1-3.16 
µg/animal) showed full efficacy after intrathecal as well as after 
intracerebroventricular administration (ED50 0.42 µg/animal i.t., 0.18 µg/animal 
i.c.v.). Combined administration of equianalgesic doses revealed 
spinal-supraspinal synergy (ED50 0.053 µg/animal i.t. + i.c.v.). Morphine 
(0.001-10 µg/animal) also showed central efficacy and synergy (ED50 0.547 
µg/animal i.t., 0.004 µg/animal i.c.v., 0.014 µg/animal i.t. + i.c.v.). 
Supraspinal potencies of tapentadol and morphine correlated with the 50-fold 
difference in their MOR affinities. In contrast, spinal potencies of both drugs 
were similar and correlated with their relative systemic potencies (ED50 0.27 
mg/kg i.p. tapentadol, 1.1 mg/kg i.p. morphine). Spinal administration of the 
opioid antagonist naloxone or the α2-adrenoceptor antagonist yohimbine before 
systemic administration of equianalgesic doses of tapentadol (1 mg/kg i.p.) or 
morphine (3.16 mg/kg i.p.) revealed pronounced influence on opioidergic and 
noradrenergic pathways for both compounds. Tapentadol was more sensitive toward 
both antagonists than was morphine, with median effective dose values of 0.75 
and 1.72 ng/animal i.t. naloxone and 1.56 and 2.04 ng/animal i.t. yohimbine, 
respectively. It is suggested that the antihyperalgesic action of systemically 
administered tapentadol is based on opioid spinal-supraspinal synergy, as well 
as intrinsic spinally mediated MOR-NRI synergy.

DOI: 10.1124/jpet.113.207704
PMID: 24051022 [Indexed for MEDLINE]


2. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2010 May;30(5):509-12.

[Effect and mechanism of reserpine for changing salivary protein secretion in 
Pi-deficient rats].

[Article in Chinese]

Lin CQ(1), Chen YL, Li RL.

Author information:
(1)Gastrointestinal Institute of Guangzhou University of Traditional Chinese 
Medicine, Guangzhou.

OBJECTIVE: To study the effect of reserpine (RSP) for changing salivary protein 
secretion in Pi-deficient rats and to explore its possible mechanism.
METHODS: Twenty rats allocated in the RSP group were given subcutaneous 
injection of RSP [0.4 mg/(kg x d)] for 9 successive days, while the other 20 
rats in the control group were injected with same volume of saline instead. On 
the 10th day, ten rats randomly selected from each group were subjected for 
extracting saliva to detect salivary amylase activity (sAA) before and after an 
acid stimulation; and drawing blood from the orbital vein to measure the 
contents of vasoactive intestinal peptide (VIP) and cyclic adenosine 
monophosphate (cAMP). Then they were sacrificed and their parotids were taken 
out for pathological examination with HE staining, as well as for VIP and cAMP 
measuring, and zymogen granules counting under a transmission electron 
microscope. The remainder animals were stopped injecting and normally fed to 40 
days, then subjected to be detected as above-mentioned.
RESULTS: Food intake and body weight reduction were more significantly in the 
RSP group than in the control group. On the 10th day, the ratio of sAA 
before/after stimulation in the RSP group was 0.39 +/- 0.18, significantly lower 
than that in the control group (0.80 +/- 0.21, P < 0.01), but it was restored 
rapidly, reaching the normal range on the 25th day, on the 40th day, it became 
significantly different to the level on the 10th day (P < 0.05) and approached 
the level in the control group (P > 0.05). No significant pathological change of 
parotid was found in both groups; but the number of zymogen granules in the RSP 
group was remarkably more than that in the control group (41.4 +/- 4.9 vs 34.6 
+/- 5.2, P < 0.01). Serum level of VIP in the RSP group was significantly less 
while that of cAMP was higher than that in the control group (22.5 +/- 13.1 mg/L 
vs 38.5 +/- 14.1 mg/L, and 125.8 +/- 15.5 micromol/L vs 105.3 +/- 16.7 
micromol/L, both P < 0.05), but no inter-group difference was found in parotid 
tissue contents of both VIP and cAMP. All the indices detected became equivalent 
in the two groups on the 40th day.
CONCLUSION: The reduction of salivary protein in Pi-deficient rats induced by 
RSP may be related to the regulatory pathway of VIP and cAMP.

PMID: 20681282 [Indexed for MEDLINE]


3. Acta Pharm Hung. 2005;75(1):3-16.

[Electrogenic Na+/Ca2+-exchange regulation by alpha2-receptor in peripheral 
sympathetic nerve].

[Article in Hungarian]

Török TL(1), Nagykáldi Z, Sáska Z, Kovács T, Nada SA, Zillikens S, Magyar K.

Author information:
(1)Semmelweis Egyetem Gyógyszerhatástani Intézete, Budapest.

Electrical depolarisation-(2 Hz, 1 ms)-induced [3H]noradrenaline ([3H]NA) 
release was measured from the isolated main pulmonary artery of the rabbit in 
the presence of uptake blockers (cocaine, 3 x 10(-5)M; corticosterone, 5 x 
10(-5)M) and after blocking the MAO-enzyme by pargyline (1,2 x 10(-4)M). 
Substitution of most of the external Na+ by Li+ (113 mM; [Na+]0: 25 mM) slightly 
potentiated the stimulation-induced release of [3H]NA in a tetrodotoxin (TTX, 
10(-7)M) sensitive manner. The reverse Na+/Ca2+-exchange inhibitor KB-R7943 (3 x 
10(-5)M) failed to inhibit the stimulation-evoked release of [3H]NA, but 
increased the resting outflow of neurotransmitter. The 'N-type' 
voltage-sensitive Ca2+-channel (VSCC) blocker omega-conotoxin (omega-CgTx) GVIA 
(10(-8)M) significantly and irreversibly inhibited the release of [3H]NA on 
stimulation (approximately 60-70%). The 'residual release' of NA was abolished 
either by TTX or by reducing external Ca2+ from 2,5 to 0,25 mM. The 'residual 
release' of NA was also blocked by the non-selective VSCC-blocker neomycin (3 x 
10(-3)M). Direct correlation was obtained between the extent of VSCC-inhibition 
and the transmitter release enhancing-effect of presynaptic alpha2-receptor 
blocker yohimbine (3 x 10(-7)M). When the release of [3H]NA was blocked by 
omega-CgTx GVIA plus neomycin, yohimbine was ineffective. Inhibition of the 
Na+-pump by removal of K+ from the external medium increased both the resting 
and the stimulation-evoked release of [3H]NA in the absence of functioning VSCCs 
(i.e. in the presence of neomycin and after omega-CgTx treatment). Under these 
conditions the stimulation-evoked release of NA was abolished either by TTX or 
by external Ca2+-removal (+1 mM EGTA). Similarly, external Li+ (113 mM) or the 
reverse Na+/Ca2+ exchange blocker KB-R7943 (3 x 10(-5)M) significantly inhibited 
the nerve-evoked release of NA in 'K+-free' solution. KB-R7943 decreased the 
resting outflow of NA as well. Under conditions, in which the Na+-pump was 
inhibited in the absence of functioning VSCCs, yohimbine (3 x 10(-7)M) further 
enhanced the release of neurotransmitter, while l-noradrenaline (l-NA, 10(-6)M), 
an agonist of presynaptic alpha2-receptors, inhibited it. The yohimbine-induced 
enhancement of NA-release was abolished by Li+-substitution and significantly 
inhibited by KB-R7943 application. It is concluded that after blockade of VSCCs, 
brief depolarising pulses may reverse Na+/Ca2+-exchange and release 
neurotransmitter in Na+-loaded sympathetic nerves. Further, similar to that of 
VSCCs, the reverse Na+/Ca2+-exchange may also be inhibited by presynaptic 
alpha2-receptor activation.

PMID: 16045199 [Indexed for MEDLINE]


4. J Wildl Dis. 2000 Apr;36(2):335-41. doi: 10.7589/0090-3558-36.2.335.

Butorphanol/xylazine/ketamine immobilization of free-ranging Baird's tapirs in 
Costa Rica.

Foerster SH(1), Bailey JE, Aguilar R, Loria DL, Foerster CR.

Author information:
(1)Division of Wildlife Health, College of Veterinary Medicine, Cornell 
University, Ithaca, New York 14853, USA. shernz@aol.com

Cardiopulmonary effects and the utility of a butorphanol/xylazine/ketamine 
combination were evaluated during twenty immobilizations of sixteen Baird's 
tapirs (Tapirus bairdii) between March 1996 and January of 1998 in Corcovado 
National Park (Costa Rica). The animals were attracted to a bait site and darted 
from tree platforms. The tapirs were estimated to weigh between 200 to 300 kg. 
Actual weights of three tapirs taken at later dates fell within the estimated 
range. A butorphanol, 48+/-1.84 (x +/- SE) mg/animal IM, and xylazine, 
101+/-2.72 mg/animal IM, combination was used to immobilize the animals. In some 
instances, ketamine was used either IM or IV at 187+/-40.86 mg/animal to prolong 
the immobilization period in addition to the butorphanol/xylazine combination. 
Naltrexone was used IM to reverse butorphanol at 257+/-16.19 mg/animal. Either 
yohimbine, 34+/-0.61 or tolazoline at 12+/-10.27 mg/animal, was used to reverse 
xylazine. The mean time from dart impact to first visible effect was 4.63+/-0.50 
min (x +/- SE). Mean time to sternal recumbency was 12.21+/-1.08 min. Mean time 
the tapirs were immobilized was 45.63+/-3.6 min. Mean time to return to sternal 
recumbency and standing in animals that received yohimbine and naltrexone was 
3.16+/-1.06 and 5.33+/-1.45 min, respectively. Mean time to return to sternal 
recumbency and standing in animals that received tolazoline and naltrexone was 
1.57+/-0.39 and 3.14+/-0.51 min, respectively. Cardiopulmonary parameters 
including heart rate, respiratory rate, body temperature, electrocardiogram, 
percent oxygen satoration, and indirect blood pressure were recorded. Arterial 
blood gas analysis was performed on four animals. A mild degree of hypoxemia was 
evidenced by low arterial oxygen saturations. Five of 14 (36%) animals measured 
had oxygen saturations below 90%. Bradycardia (heart rates <45 BPM) was an 
expected finding in 11 (55%) immobilizations. Induction, recovery and muscle 
relaxation of each immobilization was graded. Premature arousal, which occurred 
in six (30%) animals, was the only problem associated with the immobilizations. 
Butorphanol/xylazine is a recommended protocol for immobilization of calm, 
free-ranging tapirs lasting less than 30 min. Supplemental intravenous 
administration of ketamine is recommended for longer procedures. Nasal 
insufflation of oxygen is recommended.

DOI: 10.7589/0090-3558-36.2.335
PMID: 10813616 [Indexed for MEDLINE]


5. Circulation. 1994 Aug;90(2):895-907. doi: 10.1161/01.cir.90.2.895.

Coronary vasoconstriction after percutaneous transluminal coronary angioplasty 
is attenuated by antiadrenergic agents.

Gregorini L(1), Fajadet J, Robert G, Cassagneau B, Bernis M, Marco J.

Author information:
(1)Clinica Medica Generale, Università di Milano, Italy.

BACKGROUND: Vasoconstriction occurs after percutaneous transluminal coronary 
angioplasty (PTCA) along the dilated vessel. The vasomotor changes, initiated by 
the mechanical stretch of the stenotic region, are thought to be due to various 
mechanisms but whether the sympathetic nervous system plays a role in this 
phenomenon remains unknown.
METHODS AND RESULTS: Quantitative angiography (ARTREK) was performed in 45 
patients undergoing an epicardial vessel PTCA for a stenosis of 76 +/- 1% (1) in 
basal conditions, (2) after PTCA, and (3) 30 minutes after PTCA 
(vasoconstriction). In 14 control patients, the same measurements were obtained 
up to 60 minutes after PTCA. Coronary diameters were measured along the PTCA 
vessel at the narrowest stenosis level and at a level peripheral to stenosis. In 
36 patients two diameters were also measured at a proximal segment and at a 
distal segment along a nonmanipulated vessel. Thirty minutes after PTCA the 
dilated segment underwent a -31 +/- 2% (mean +/- SEM, ANOVA, P < .05) reduction 
in diameter when compared with PTCA values, and the segment peripheral to 
stenosis showed a reduction of -17 +/- 2% (P < .05). In all patients a 
significant vasoconstriction also was observed along the control vessel 
(proximal segment, -14 +/- 3%; P < .05 versus basal; and distal segment, -17 +/- 
2%). At the time of maximal vasoconstriction (30 minutes after PTCA), the 
patients (treatment groups) received (1) 18 micrograms/kg IC phentolamine (Phe, 
n = 7), (2) 14 micrograms/kg IC yohimbine (YO, n = 7), (3) 16 micrograms/kg IC 
propranolol (Pro) followed by 18 micrograms/kg IC phentolamine (Pro+Phe, n = 7), 
and (4) 0.2 mg/kg IC bretylium (Bre, n = 10). In 14 patients (control groups) an 
intracoronary injection of warm saline was given. After drug injections, 
angiograms were repeated at 5-minute intervals for 20 minutes and ended after a 
300-micrograms intracoronary trinitroglycerin injection. At stenosis level, Phe 
and Bre counteracted vasoconstriction, inducing a dilatation of +19 +/- 3% and 
+22 +/- 6%, respectively, while Pro+Phe caused a dilatation of +16 +/- 9% above 
the PTCA values (P < .05 versus PTCA). YO only partially reversed 
vasoconstriction (from -33 +/- 4% to -12 +/- 4%, P = NS versus PTCA). At 
peripheral-to-stenosis level, vasoconstriction was abolished by Phe (+26 +/- 7%, 
P < .05 versus basal), while it was still present after Pro+Phe (-23 +/- 2%) and 
Bre (-18 +/- 4%). In addition, Phe and Bre dilated the control vessel at the 
proximal segment (+17 +/- 6% and +8 +/- 4%, respectively, P < .05 versus basal), 
while YO and Pro+Phe only counteracted vasoconstriction (from -15 +/- 3% to +7.6 
+/- 1% and from -16 +/- 3% to +4 +/- 5%, respectively, P = NS versus basal). At 
the distal segment only Phe produced a vasodilatation of +23 +/- 1%; YO 
counteracted constriction (from -16 +/- 2% to +9 +/- 6%, P < .05 versus basal), 
whereas after Pro+Phe and Bre, the vasoconstriction persisted.
CONCLUSIONS: The mechanical stretch and ischemia caused by balloon inflation 
induced vasoconstriction mediated by alpha-adrenergic receptors (mainly alpha 
1), overcoming a beta-mediated dilatation. The use of different antiadrenergic 
drugs showed that Phe counteracts post-PTCA vasoconstriction, and the 
simultaneous use of alpha- and beta-receptor blocking agents (Pro+Phe and Bre) 
reveals the presence of a peripheral, predominant beta-mediated dilatation. The 
presence of vasoconstriction also along the control vessels not branching from 
the stretched ramus provides evidence for the existence of neural sympathetic 
vasoconstrictor reflexes.

DOI: 10.1161/01.cir.90.2.895
PMID: 8044961 [Indexed for MEDLINE]