Search

Background: Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel implicated in pain sensation in response to heat, protons, and capsaicin (CAPS). It is well established that TRPV1 is involved in mechanical allodynia. This study investigates the effect of Ononis spinosa (Fabaceae) in CAPS-induced mechanical allodynia and its mechanism of action. Methods: Mechanical allodynia was induced by the intraplantar (ipl) injection of 40 µg CAPS into the left hind paw of male Wistar rats. Animals received an ipl injection of 100 µg O. spinosa methanolic leaf extract or 2.5% diclofenac sodium 20 minutes before CAPS injection. Paw withdrawal threshold (PWT) was measured using von Frey filament 30, 90, and 150 minutes after CAPS injection. A molecular docking tool, AutoDock 4.2, was used to study the binding energies and intermolecular interactions between O. spinosa constituents and TRPV1 receptor. Results: The ipsilateral ipl injection of O. spinosa before CAPS injection increased PWT in rats at all time points. O. spinosa decreased mechanical allodynia by 5.35-fold compared to a 3.59-fold decrease produced by diclofenac sodium. The ipsilateral pretreatment with TRPV1 antagonist (300 µg 4-[3-Chloro-2-pyridinyl]-N-[4-[1,1-dimethylethyl] phenyl]-1-piperazinecarboxamide [BCTC]) as well as the ß2-adrenoreceptor antagonist (150 µg butoxamine) attenuated the action of O. spinosa. Depending on molecular docking results, the activity of the extract could be attributed to the bindings of campesterol, stigmasterol, and ononin compounds to TRPV1. Conclusions: O. spinosa alleviated CAPS-induced mechanical allodynia through 2 mechanisms: the direct modulation of TRPV1 and the involvement of ß2 adrenoreceptor signaling. [ABSTRACT FROM AUTHOR]

We previously obtained evidence suggesting that physical exercise increases the release of L-carnosine (CAR) from muscles and that CAR affects autonomic neurotransmission and physiological phenomena in rats. It has also been reported that exercise elicits an increase in activity of the sympathetic nerve innervating the skeletal muscle. Therefore, in this study, we investigated the effect of CAR application, onto the surface of the right femoral muscle, on activity of the sympathetic nerve innervating the left femoral muscle, in urethane-anesthetized rats. Topical application of 10 pg (44.2 fmol) of CAR increased either skeletal muscle sympathetic nerve activity (skeletal muscle-SNA) or skeletal muscle blood flow (skeletal muscle-BF) of the contralateral skeletal muscle. Furthermore, thioperamide, a histamine H3-antagonist, inhibited the increase in skeletal muscle-SNA, and butoxamine, a β2-antagonist, abolished the increase in skeletal muscle-BF caused by topical application of CAR. The present results suggest that CAR released from muscles during physical exercise might affect skeletal muscle-SNA and skeletal muscle-BF on the opposite side of the body via a CAR evoked effect in muscles. [ABSTRACT FROM AUTHOR]

Objective: This study investigated the involvement of α1- and β2-adrenergic receptors in skeletal muscle blood flow changes during variations in ETCO2., Methods: Forty Japanese White rabbits anesthetized with isoflurane were randomly allocated to 1 of 5 groups: phentolamine, metaproterenol, phenylephrine, butoxamine, and atropine. Heart rate (HR), systolic blood pressure (SBP), common carotid artery blood flow (CCBF), masseter muscle tissue blood flow (MBF), and quadriceps muscle tissue blood flow (QBF) were recorded and analyzed at 3 periods: (1) baseline, (2) during hypercapnia (phentolamine and metaproterenol groups) or hypocapnia (phenylephrine, butoxamine, and atropine groups), and (3) during or after receiving vasoactive agents., Results: MBF and QBF decreased during hypercapnia. The decrease in MBF was smaller than that in QBF. SBP and CCBF increased, while HR decreased. Both MBF and QBF recovered to their baseline levels after phentolamine administration. MBF became greater than its baseline level, while QBF did not fully recover after metaproterenol administration. MBF and QBF increased during hypocapnia. The increase rate in MBF was larger than that in QBF. HR, SBP, and CCBF did not change. Both MBF and QBF decreased to ∼90% to 95% of their baseline levels after phenylephrine or butoxamine administration. Atropine showed no effects on MBF and QBF., Conclusion: These results suggest the skeletal muscle blood flow changes observed during hypercapnia and hypocapnia may mainly involve α1-adrenergic but not β2-adrenergic receptor activity., (© 2023 by the American Dental Society of Anesthesiology.)

Background: This present study was undertaken to determine whether beta-blockers produce the cutaneous analgesic effect, comparing them with the long-acting local anesthetic bupivacaine., Methods: Using a rat model of infiltrative cutaneous analgesia, the effect of 5 beta-blockers (oxprenolol, carteolol, butaxamine, metoprolol, and acebutolol) and bupivacaine was compared and eventually combined with epinephrine., Results: Among 5 beta-blockers, oxprenolol exhibited the most potent and the longest duration of cutaneous analgesia. In dose-response studies, the rank order of efficacy (ED 50 [50% effective dose]) was bupivacaine (0.40 [0.35-0.47] μmol) > oxprenolol (2.33 [2.06-2.64] μmol) > carteolol (4.86 [4.27-5.53] μmol) ( p < 0.01). Carteolol provoked a longer duration of analgesia ( p < 0.01) than oxprenolol or bupivacaine on an equipotent basis (ED 25 , ED 50 , and ED 75 ). Adding epinephrine 1:200,000 to drug preparations (carteolol, oxprenolol, and bupivacaine) at ED 95 had a peripheral action in prolonging the duration of action., Conclusions: Oxprenolol and carteolol had greater potencies and longer durations of cutaneous analgesia than butaxamine, metoprolol, and acebutolol. Oxprenolol produced a similar duration of action when compared to bupivacaine, while carteolol had a greater duration of action than bupivacaine. Cutaneous analgesia of oxprenolol (or carteolol) plus adrenaline was greater than that of bupivacaine plus adrenaline.

Abstract: Recent studies have shown that osteoblasts and osteoclasts express β2-adrenoceptor, and increased sympathetic nervous activity causes bone loss via an increase in osteoclastic bone resorption and a decrease in osteoblastic bone formation. We previously demonstrated that non-selective β-adrenoceptor antagonist propranolol at low doses (0.1 and 1mg/kg), but not at a higher dose (10mg/kg), prevented a decrease in bone mass and an increase in bone fragility in spontaneously hypertensive rat (SHR), an animal model of osteoporosis with hyperactivity of the sympathetic nervous system, without affecting blood pressure. In the present study, the dose effects of butoxamine, a selective β2-adrenoceptor antagonist, on bone metabolism were examined in SHR by analysis of microcomputed tomography, bone histomorphometry, biomechanical testing and plasma biochemistry. Treatment of SHR with butoxamine at 0.1, 1 and 10mg/kg (per os) for 12 weeks increased bone mass indices and biomechanical parameters of strength and toughness of the lumbar vertebrae, suggesting antiosteoporotic activity. Butoxamine dose-dependently decreased osteoclast number and surface per bone surface with decreases in plasma tartrate-resistant acid phosphatase-5b level, a biochemical index of osteoclastic activity. On the other hand, histomorphometry indices of bone formation and plasma osteocalcin concentration reflecting osteoblastic activity were increased in SHR treated with butoxamine at 0.1 and 1mg/kg, but not at 10mg/kg. These results suggest that β-adrenoceptor antagonists at a low dose may improve osteoporosis with hyperactivity of the sympathetic nervous system via β2-adrenoceptor blocking action, while they may have a somewhat inhibitory effect on osteoblastic activity at a high dose. [Copyright &y& Elsevier]

Abstract: The recently reported X-ray structure of the Beta2-adrenergic receptor, the first reported crystal structure of a ligand-mediated GPCR, is used to explore its utility in computer-aided drug design. Validations were conducted with known beta blockers. This was followed by high-throughput docking studies with proprietary and commercial databases to further validate the X-ray structure’s usefulness as a design tool and to explore the potential for discovery of novel chemical classes acting as Beta2 inhibitors. Our results include the finding of ligands with traditional beta-blocker motifs as well as new motifs, thereby serving to both validate the approach and project its usefulness in the finding and design of novel compounds. [Copyright &y& Elsevier]

Abstract: Adaptations to the chronic administration of opioids reduce the utility of these drugs in treating pain and support addiction. Recent genetics-based approaches have implicated the β2 adrenergic receptor (β2-AR) in controlling some of these responses. We do not know, however, whether this receptor can modulate tolerance, dependence or changes in gene expression caused by chronic opioid administration. For our studies we used C57BL/6 mice and β2-AR knockout mice in the FVB background. Morphine dose–response relationships were established both prior to and after chronic morphine treatment. In some cases, the selective β2-AR antagonist butoxamine was administered along with or after morphine. Physical dependence was assessed using naloxone-precipitated withdrawal. The expression of calcitonin gene related peptide (CGRP) and substance P (SP) were measured in spinal cord and dorsal root ganglion (DRG) tissues using both real-time PCR and enzyme-linked immunoassay (ELISA). Both the co-administration of butoxamine with morphine and the administration of butoxamine after chronic morphine reversed morphine tolerance. Morphine failed to cause tolerance in β2-AR knockout mice. Physical dependence was reduced under the same circumstances. The chronic administration of butoxamine with morphine reduced or eliminated the normally observed up-regulation of CGRP and SP in spinal cord and DRG tissues. Our results suggest that the β2-AR modulates both opioid tolerance and physical dependence. Activation of β2-ARs appears to be required for some of the key neurochemical changes which characterize chronic opioid administration. Therefore, β2-AR antagonists show some promise as agents to enhance chronic opioid analgesic therapy. [Copyright &y& Elsevier]

1 The present study was carried out to pharmacologically identify theβ-adrenoceptor subtype that mediates isoprenaline-elicited relaxation in the isolated guinea-pig tracheal smooth muscle, to answer the question whether it isβ1- orβ2-subtype?2 Isoprenaline as well as salbutamol, a well-knownβ2-selective adrenoceptor agonist, produced a concentration-dependent relaxation with a pD2 value of 8.12vs.7.54 for salbutamol.3 Isoprenaline-elicited relaxation was not affected byβ1-selective antagonists, atenolol and CGP-20,712A, within the concentration ranges supposed to antagonizeβ1-subtype: atenolol,≤10−6 m; CGP-20,712A,≤10−8 m.4 By contrast, the concentration–response curves for isoprenaline as well as salbutamol were shifted rightwards in a competitive fashion by atenolol at the concentrations≥3 × 10−6 m. However, pA2 values of atenolol against isoprenaline (5.86) and salbutamol (5.71) were consistent with the value corresponding toβ2- but not toβ1-subtype (around 7.00), and these values were not significantly different from each other.5 Competitive antagonism of the relaxations to isoprenaline and salbutamol were also obtained withβ2-selective antagonists, butoxamine and ICI-118,551. Against isoprenaline and salbutamol, the pA2 values of butoxamine (6.51vs.6.81) and ICI-118,551 (8.83vs.8.90) were substantially identical. Thus the primary mediation ofβ2-receptor in the relaxations was strongly supported.6 The present findings provide evidence that theβ-adrenoceptor which mediates isoprenaline-elicited relaxation of guinea-pig tracheal smooth muscle is essentiallyβ2- but notβ1-subtype. The present study also indicates the importance of using multiple receptor antagonists with different pA2 values to pharmacologically identify the responsible receptor subtype in smooth muscle mechanical responses. [ABSTRACT FROM AUTHOR]

This study investigated adrenoreceptor-mediated responses of muscularis mucosae from the fundic and antral ends of the rabbit gastric corpus. Norepinephrine-induced fundic muscularis mucosae contractions were enhanced by propranolol and converted to relaxations by phentolamine. Methoxamine, but not clonidine, elicited large fundic contractions. Fundic muscle responded to low isoproterenol concentrations with atenolol- and butoxamine-resistant relaxations, and to high concentrations with atenolol-sensitive contractions. Norepinephrine evoked propranolol-resistant relaxations of antral muscularis mucosae that were enhanced by phentolamine. Methoxamine and clonidine elicited small antral contractions. Lower concentrations of isoproterenol caused atenolol-resistant antral relaxations that were enhanced by butoxamine; higher concentrations produced weak excitation. Fundic and antral relaxations to isoproterenol were abolished by cyanopindolol. Fundic muscularis mucosae possesses excitatory alpha1-, beta1- and inhibitory beta3-adrenoreceptors. Excitatory beta2- and inhibitory beta3-adrenoreceptors predominate in the antral region. The heterogeneous adrenoreceptor-mediated responses of the gastric muscularis mucosae suggest that adrenergic modulation of its motor activity is unlikely to be linked to acid secretion. [ABSTRACT FROM AUTHOR]

Recent studies have reported a relationship between periodontal disease and hypertension, and previous evidence suggests that the sympathetic nervous system plays an important role in the control of bone metabolism. This study sought to evaluate the effect of the beta-2 adrenergic receptor (β2-AR) blocker butoxamine on experimental periodontitis in a rat model. Wistar-Kyoto and spontaneously hypertensive rats (n = 6 per group) were orally administered butoxamine 1 mg/kg/day and experimental periodontitis was induced by applying an orthodontic ligature wire. The rats were sacrificed after 4 weeks and the residual alveolar bone was measured using micro-computed tomography (micro-CT) imaging analysis software for histological analysis. Micro-CT imaging analysis showed a higher ratio of residual alveolar bone, BV/TV, and Tb.N in both Wistar-Kyoto and spontaneously hypertensive rats treated with butoxamine compared with the corresponding control rats. In histological analysis, compared with the Wistar-Kyoto and spontaneously hypertensive rat control groups, the corresponding butoxamine-treated groups showed a lower ratio of attachment level, lower values of osteoclast number and surface. β2-AR blockers maintained the alveolar bone mass and attachment level by suppressing osteoclast activity. Thus, β2-AR blockers may be effective in preventing periodontitis. • β2-AR blockers suppressed the expression of the cytokines TNF-α, IL-1β, and IL-6. • β2-AR blockers suppressed the activity of osteoclasts and sympathetic nerve fibers. • β2-AR blockers maintained alveolar bone mass and attachment level. • β2-AR blockers may be effective in preventing periodontitis. • Sympathicotonia is associated with increased severity of periodontitis. [ABSTRACT FROM AUTHOR]

Objective: Regulation of bone metabolism by the sympathetic nervous system has recently been clarified. Tooth movement is increased by increased bone metabolic turnover due to sympathetic activation. This study aimed to compare the effects of the β-adrenergic receptor (β-AR) blockers atenolol (β1-AR blocker), butoxamine (β2-AR blocker) and propranolol (non-selective β-AR blocker) on tooth movement in spontaneously hypertensive rats (SHR) with sympathicotonia., Materials and Methods: Spontaneously hypertensive rats were divided into the following four groups: an SHR control group and groups treated with 0.1 mg/kg atenolol, 1 mg/kg butoxamine or 1 mg/kg propranolol (n = 6 rats/group). Atenolol, butoxamine or propranolol was administered daily to each treatment group, and orthodontic force was applied using a closed-coil spring. Finally, immunohistochemical analysis was performed for receptor activator of nuclear factor kappa-B ligand (RANKL) and sclerostin (SOST)., Results: Atenolol, butoxamine and propranolol inhibited tooth movement and increased maxillary alveolar bone volume. Histological analysis revealed that these β-AR blockers decreased osteoclast activity on the compression side. Furthermore, immunohistochemical analysis revealed that atenolol, butoxamine and propranolol decreased the number of RANKL- and SOST-positive osteocytes on the compression side., Conclusions: β-AR blockers decreased tooth movement and downregulated SOST in osteocytes, accompanied by increasing alveolar bone resorption., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd. All rights reserved.)

Intravenous or intracerebroventricular administration of thyrotropin-releasing hormone (TRH) significantly improved survival in immunized mice subjected to fatal anaphylaxis by intravenous challenge with an antigen. This protective action of TRH was blocked by pretreatment with the beta-adrenergic antagonist propranolol (5 mg/kg), or by prior administration of the cardioselective beta 1-antagonist, metoprolol (5 mg/kg), but not by pretreatment with the beta 2-selective antagonist, butoxamine (5 mg/kg). It is suggested, based on the present and previous findings that the anti-anaphylactic effect of TRH in the mouse is mediated through activation of beta 1-adrenoceptive effectors, secondary to central stimulation of sympathomedullary release of catecholamines.