Nefopam but not physostigmine affects the thermoregulatory response in mice via α2-adrenoceptors

Höcker, Jan; Gruenewald, Matthias; Meybohm, Patrick; Schaper, C.; Scholz, Jens; Steinfath, Markus; Bein, Berthold

doi:10.1016/j.neuropharm.2009.09.001

Cited by 6 publications

(7 citation statements)

References 39 publications

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“…Interestingly, the anti-shivering effect of nefopam was reported to be related to the alpha-2 receptor in a recent animal study [16]. Therefore, although nefopam's analgesia was not completely reversed by blockade of the alpha-2 receptor, the results of this study could provide the initiative for further investigation into the possible interaction of nefopam with alpha-2 agonists, as both are widely used in the care of patients during the perioperative period.…”

Section: Discussionmentioning

confidence: 75%

“…Although alpha-adrenergic agents are being widely employed in the perioperative period, the role of noradrenergic modulation in the analgesic effect of nefopam has not been fully addressed. Furthermore, a recent study also demonstrated the important role of the alpha-2 receptor in the anti-shivering effect of nefopam, suggesting the possibility that the alpha-2 receptor is involved in nefopam's mechanism of analgesia [16]. …”

Section: Introductionmentioning

confidence: 99%

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Spinal Noradrenergic Modulation and the Role of the Alpha-2 Receptor in the Antinociceptive Effect of Intrathecal Nefopam in the Formalin Test

et al. 2014

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BackgroundNefopam has shown an analgesic effect on acute pain including postoperative pain. The reuptake of monoamines including serotonin and noradrenaline has been proposed as the mechanism of the analgesic action of nefopam, but it remains unclear. Although alpha-adrenergic agents are being widely used in the perioperative period, the role of noradrenergic modulation in the analgesic effect of nefopam has not been fully addressed.MethodsChanges in the antinociceptive effect of intrathecal (i.t.) nefopam against formalin-elicited flinching responses were explored in Sprague-Dawley rats pretreated with i.t. 6-hydroxydopamine (6-OHDA), which depletes spinal noradrenaline. In addition, antagonism to the effect of nefopam by prazosin and yohimbine was evaluated to further elucidate the antinociceptive mechanism of i.t. nefopam.ResultsPretreatment with i.t. 6-OHDA alone did not alter the flinching responses in either phase of the formalin test, while it attenuated the antinociceptive effect of i.t. nefopam significantly during phase 1, but not phase 2. The antagonist of the alpha-2 receptor, but not the alpha-1 receptor, reduced partially, but significantly, the antinociceptive effect of i.t. nefopam during phase 1, but not during phase 2.ConclusionsThis study demonstrates that spinal noradrenergic modulation plays an important role in the antinociceptive effect of i.t. nefopam against formalin-elicited acute initial pain, but not facilitated pain, and this action involves the spinal alpha-2 but not the alpha-1 receptor.

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Section: Discussionmentioning

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Spinal Noradrenergic Modulation and the Role of the Alpha-2 Receptor in the Antinociceptive Effect of Intrathecal Nefopam in the Formalin Test

et al. 2014

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“…The inverted enantiomer 55P0250 lacked comparable effects not only on blood glucose and receptor binding, but also on oxygen saturation (Figure A). The α 2 ‐adrenoceptor, including its α 2A ‐subtype, is known to be involved in thermoregulation by stimulating vasoconstriction in thermoregulatory tissues like human skin and, as relevant here, rodent tail . Although a contribution of effects mediated via α 1 ‐adrenoceptors cannot be excluded, increased oxygen saturation observed in tail blood from 55P0251‐treated mice could reflect vasodilation due to α 2 ‐adrenoceptor antagonism in vivo.…”

Section: Resultsmentioning

confidence: 85%

“…The α 2 -adrenoceptor, including its α 2A -subtype, is known to be involved in thermoregulation by stimulating vasoconstriction in thermoregulatory tissues like human skin and, as relevant here, rodent tail. [25][26][27][28] Although a contribution of effects mediated via α 1 -adrenoceptors cannot be excluded, increased oxygen saturation observed in tail blood from 55P0251-treated mice could reflect vasodilation due to α 2 -adrenoceptor antagonism in vivo. Using agents that act as vasodilators via other molecular targets (carvedilol, molsidomine), we confirmed that increased oxygen saturation in tail blood is a typical attribute of vasodilation in our experimental setup ( Figure 6B).…”

Section: Pharmacokinetics Account For Divergent Activities In Vivo mentioning

confidence: 99%

Evidence that the multiflorine‐derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α₂‐adrenoceptors in mice

Lehner

Stadlbauer

Brunmair

et al. 2019

Diabetes Obesity Metabolism

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Aims To investigate the mechanism of action of 55P0251, a novel multiflorine‐derived substituted quinazolidine that augments insulin release and lowers blood glucose in rodents, but does not act via mechanisms addressed by any antidiabetic agent in clinical use. Materials and Methods Using male mice, we determined the effects of 55P0251 on glucose tolerance, insulin secretion from isolated islets and blood oxygen saturation, including head‐to‐head comparison of 55P0251 to its inverted enantiomer 55P0250, as well as to other anti‐hyperglycaemic multiflorine derivatives discovered in our programme. Results 55P0251 was clearly superior to its inverted enantiomer in the glucose tolerance test (area under the curve: 11.3 mg/kg 55P0251, 1.19 ± 0.04 min*mol/L vs 55P0250, 1.80 ± 0.04 min*mol/L; P < .0001). For insulin release in vitro, this superiority became visible only under concomitant adrenergic background stimulation (glucose‐stimulated insulin release, fmol*islet−1*30 min−1: without α2‐adrenoceptor agonist: 500 μmol/L 55P0251, 390 ± 34, vs 55P0250, 459 ± 40, nonsignificant; with α2‐adrenoceptor agonist: 250 μmol/L 55P0251, 138 ± 9, vs 55P0250, 21 ± 6; P < .0001). Since receptor binding assays suggested antagonism at α2A‐adrenoceptors as a potential mechanism of action, we measured oxygen saturation in capillary blood from the tail as a surrogate of vasoconstriction, which supported α2‐antagonistic action in vivo (90 mg/kg 55P0251, 83 ± 3%, vs 55P0250, 57 ± 3%; P < .0001). Lack of association between glucose‐lowering activities and α2A‐adrenoceptor binding affinity arising from comparison of multiflorine derivatives was attributed to differences in their pharmacokinetic properties. Conclusions Our findings suggest that 55P0251 and related multiflorine derivatives are to be categorized as α2‐adrenoceptor antagonists with potential to lower blood glucose by blocking α2A‐adrenoceptors on pancreatic β cells.

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“…It is presumed, however, that it inhibits the synaptic reuptake of dopamine, norepinephrine, and serotonin, as amphetamine does. Moreover, it has been suggested to be involved in the thermoregulatory response via α2 adrenoceptors [27,28].…”

Section: Adverse Effects Of Nefopammentioning

confidence: 99%

Adverse Hemodynamic Effects of Nefopam in Patients Undergoing Plastic and Aesthetic Surgery: A Single-Center Retrospective Study

Choi

Kim

et al. 2018

Arch Aesthetic Plast Surg

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Background Nefopam is used to improve postoperative hypothermia in the field of plastic and aesthetic surgery. However, there is a paucity of data about its adverse hemodynamic effects and safety. We therefore assessed its adverse hemodynamic effects in patients undergoing plastic and aesthetic surgery. Methods We conducted a single-center retrospective study of 148 patients, in whom we measured hemodynamic parameters using sphygmomanometry (systolic blood pressure [SBP], diastolic blood pressure [DBP], arterial blood pressure [ABP], and heart rate [HR]). Moreover, we also assessed myocardial oxygen demand using the rate pressure product (RPP). Results The patients included 96 men and 52 women, with a mean age of 34.7±8.5 years. There were no significant differences in SBP, DBP, ABP, HR, or RPP before and after nefopam administration (P>0.05). However, a significant difference was found in the number of the patients with an HR of >100 beats per minute or with an RPP of >12 U before and after nefopam administration (P=0.001). Conclusions Surgeons should consider the possibility of tachycardia and increased blood pressure in the management of postoperative hypothermia in patients with cardiac arrhythmia, ischemic heart disease, or essential hypertension. Nonetheless, further prospective, large-scale, multi-center, randomized, controlled studies are warranted to confirm our results.

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Nefopam but not physostigmine affects the thermoregulatory response in mice via α2-adrenoceptors

Cited by 6 publications

References 39 publications

Spinal Noradrenergic Modulation and the Role of the Alpha-2 Receptor in the Antinociceptive Effect of Intrathecal Nefopam in the Formalin Test

Spinal Noradrenergic Modulation and the Role of the Alpha-2 Receptor in the Antinociceptive Effect of Intrathecal Nefopam in the Formalin Test

Evidence that the multiflorine‐derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α₂‐adrenoceptors in mice

Adverse Hemodynamic Effects of Nefopam in Patients Undergoing Plastic and Aesthetic Surgery: A Single-Center Retrospective Study

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Nefopam but not physostigmine affects the thermoregulatory response in mice via α2-adrenoceptors

Cited by 6 publications

References 39 publications

Spinal Noradrenergic Modulation and the Role of the Alpha-2 Receptor in the Antinociceptive Effect of Intrathecal Nefopam in the Formalin Test

Spinal Noradrenergic Modulation and the Role of the Alpha-2 Receptor in the Antinociceptive Effect of Intrathecal Nefopam in the Formalin Test

Evidence that the multiflorine‐derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α2‐adrenoceptors in mice

Adverse Hemodynamic Effects of Nefopam in Patients Undergoing Plastic and Aesthetic Surgery: A Single-Center Retrospective Study

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Evidence that the multiflorine‐derived substituted quinazolidine 55P0251 augments insulin secretion and lowers blood glucose via antagonism at α₂‐adrenoceptors in mice