Disease relevance of SPIRADOLINE

• Repeated treatment with spiradoline does not induce physical dependence as evidenced by a lack of naloxone-precipitated jumping and withdrawal-induced hyperalgesia [1].
• A dose-related accentuation of ethanol-induced motor incoordination was observed after direct cerebellar microinfusion of three kappa-opioid receptor agonists: U-50488, U-62066, and bremazocine [2].
• These results suggest that dynorphin replacement strategies, using spiradoline-like kappa-1 agonists, may have limited value in the therapy of patients with Parkinson's disease [3].
• In comparison with placebo, the lowest dose of spiradoline was associated with significant decreases in cumulative postdrug counts of total tics and phonic tics, as well as in clinician ratings of postdrug motor tic frequencies [4].
• The onset of hypotension after intrahippocampal injection of each agent was approximately 2 min and lasted approximately 30 min with U-50,488H and spiradoline and >60 min with bremazocine [5].

Psychiatry related information on SPIRADOLINE

• No differences in sensitivity were observed to the effects of spiradoline on locomotor activity [6].
• Neuroendocrine and behavioral effects of the selective kappa agonist spiradoline in Tourette's syndrome: a pilot study [4].
• In order to determine if DuP 747 has kappa-like discriminative effects it was tested for stimulus generalization in rats trained to discriminate between SC injections of saline and 3.0 mg/kg of spiradoline, a potent kappa-opioid agonist [7].
• Rats were trained in a discrete-trial avoidance/escape procedure to discriminate 1.0 mg/kg spiradoline, SC, from saline in an average of 19.7 sessions; response latencies after saline and spiradoline were not different from each other [8].
• Intake of a palatable sucrose solution modifies the actions of spiradoline, a kappa opioid receptor agonist, on analgesia and feeding behavior in male and female rats [9].

High impact information on SPIRADOLINE

• The effects of the specific opioid agonists DPDPE (delta-agonist), U-62066 (kappa-agonist) and DALDA (mu-agonist) on the hypoxia-evoked response were investigated in both a whole-gland preparation and in isolated adrenal chromaffin cells using amperometry, whole-cell patch clamping and measurement of cytosolic [Ca(2+)] [10].
• Rats received the nonpeptide kappa agonist U62, 066E, (Spiradoline, Upjohn), 10 nmoles/0.2 microl or drug vehicle bilaterally into the the hippocampus for 3 days prior to and during isolation or grouping [11].
• Inhibitory effect of spiradoline, a kappa opioid receptor agonist, on Ca2+ induced contraction and the intracellular Ca2+ concentration in porcine coronary artery [12].
• DESIGN--The inhibitory effect of spiradoline was investigated (1) on the contractile response of pig coronary artery to the readmission of Ca2+, following initial exposure to Ca2+ free medium and depolarisation with 40 mM K+; (2) on the intracellular Ca2+ concentration as assessed using the fluorescent calcium indicator fura-2 [12].
• STUDY OBJECTIVE--The aim was to clarify the inhibitory effect of the selective kappa agonist, spiradoline, on coronary arterial smooth muscle in relation to the intracellular Ca2+ concentration [12].

Biological context of SPIRADOLINE

• CONCLUSIONS: These results demonstrate that females are more sensitive than males to the CHS-altering effects of spiradoline and that sex differences in the magnitude and direction of opioid-induced sex differences are outcome dependent [13].
• In pentazocine- or spiradoline-dependent rats, naloxone (2 mg/kg) did not induce up-regulation of brain PKC-alphabeta [14].
• Spiradoline dose dependently displaced [3H]DPN from membranes prepared from early and late cells revealing both high (Ki[H]) and low (Ki[L]) affinity binding sites [15].
• In isolated rat hearts, spiradoline reduced heart rate and cardiac contractility and increased the PR interval and QRS width of the ECG in a concentration-dependent manner [16].
• Similar to the delta-opioid receptor agonists, food intake was elevated by the kappa-opioid receptor agonist (U-50488H and U-62066) in a dose-dependent manner [17].

Anatomical context of SPIRADOLINE

• The inhibition of norepinephrine release and cAMP accumulation in the iris ciliary body by ICI and spiradoline suggests that there are both pre- and postjunctional sites of action for kappa agonists [18].
• In summary, BRE and SPR increased ANP levels in aqueous humor of rabbits, in part, via activation of K+(ATP) channels that are assumed to be associated with kappa opioid receptors [19].
• Spiradoline at low concentrations ranging from 2 x 10(-9) to 2 x 10(-7) M reduced spontaneous contractions in rabbit ileum [20].
• 6. It is suggested that the anti-arrhythmic effects of U-62066 and (-)-bremazocine are associated with the activation of peripheral kappa opioid receptors and do not depend on the activation of kappa opioid receptors in the autonomic nervous system [21].
• Electrical stimulation of the left ventricle suggested that spiradoline may exert its antiarrhythmic action by blockade of myocardial sodium currents [16].

Associations of SPIRADOLINE with other chemical compounds

• The effects of U50,488, but not spiradoline, were enhanced to a lesser degree by the 5-HT1A receptor agonist 8-OH-DPAT [22].
• Effects of the kappa opioid agonists, spiradoline (U62,066), enadoline (CI-977) and U69,593, were examined alone and in combination with the opioid antagonists quadazocine and beta-funaltrexamine in squirrel monkeys that responded under a schedule of shock titration [23].
• Two kappa agonists, U50,488 and spiradoline, produced dose-related acute decreases in both morphine and cocaine self-administration in rats; higher doses of both agents were required to decrease rates of bar-pressing for water [24].
• Pretreatment of the mice with imipramine, desipramine or clomipramine caused marked potentiation of spiradoline analgesia, whereas reserpine and phenoxybenzamine inhibited it [25].
• In contrast, sex differences were not consistently observed with the kappa-opioid receptor agonists spiradoline, (5,7,8b)-N-methyl-N[2-1(1-pyrrolidinyl),1-oxaspiro[4,5]dec-8-yl benzeneacetamide (U69593), trans-(+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide (U50488), enadoline, ethylketocyclazocine, and nalorphine [26].

Gene context of SPIRADOLINE

• Neither the kappa agonist spiradoline or the Delta agonist [D-Pen(2), D-Pen(5)]enkephalin (DPDPE) modulated the voltage gated calcium currents in cardiac vagal neurons [27].
• One objective of this study was to determine if the discriminative effects of spiradoline, a kappa-opioid agonist, are mediated by 5-HT2 receptors in rats also [28].

Analytical, diagnostic and therapeutic context of SPIRADOLINE

• In particular, (2S)-2-[(dimethylamino)methyl]-1-[(5,6,7,8-tetrahydro-5-oxo-2- naphthyl)acetyl]piperidine (34) was found to have a potency similar to spiradoline in animal models of antinociception after subcutaneous administration, with ED50s of 0.47 and 0.73 mumol/kg in the mouse and in the rat abdominal constriction tests, respectively [29].
• These results suggest that excitation of noradrenergic and serotonergic pathways in the brain appears to be involved in spiradoline analgesia, and that, as regards tail-pinch nociception, the kappa-opioid agonist acts on the noradrenergic pathway more potently than morphine [25].
• Microinjection of U-62066 (100 microg), a kappa-opioid receptor agonist, into the VLO had no effect on the allodynia [30].
• 1. The mechanism of the diuretic effect of the kappa opioid receptor agonist spiradoline was investigated in 10 healthy male subjects in a placebo-controlled, double-blind cross-over study [31].
• The electrophysiologic actions of spiradoline on sodium currents, the transient outward (i(to)) and sustained plateau potassium (ik(sus)) currents were studied in isolated cardiac rat myocytes by whole-cell patch-clamp techniques [16].

References