Elsevier

European Journal of Pharmacology

Volume 742, 5 November 2014, Pages 125-130
European Journal of Pharmacology

Neuropharmacology and analgesia
Intrathecal orphenadrine elicits spinal block in the rat

https://doi.org/10.1016/j.ejphar.2014.08.035Get rights and content

Abstract

The purpose of this study was to estimate the local anesthetic effect of orphenadrine, an anti-muscarinic agent, in spinal anesthesia and its comparison with the local anesthetic lidocaine. After the rat was injected intrathecally, the spinal block of orphenadrine and lidocaine was constructed in a dosage-dependent fashion. The potency and duration of spinal anesthesia with orphenadrine were compared with that of lidocaine. Our data demonstrated that orphenadrine and lidocaine elicited dose-dependent spinal blockades on the motor function, sensory, and proprioception. On the 50% effective dose (ED50) basis, the ranks of potency in motor function, nociception, and proprioception were orphenadrine>lidocaine (P<0.01). At equipotent doses (ED25, ED50, ED75), the block duration elicited by orphenadrine was greater than that elicited by lidocaine (P<0.01). Orphenadrine, but not lidocaine, exhibited longer duration of nociceptive/sensory blockade than that of motor blockade at equipotent doses. Ineffective-dose orphenadrine as adjuvant did not enhance spinal anesthesia with lidocaine. The preclinical data revealed that orphenadrine with a more sensory-selective action over motor block exhibited more potent and longer spinal anesthesia when compared to lidocaine.

Introduction

Orphenadrine was introduced into the market as an agent for the therapy of Parkinson׳s disease or several of the troublesome symptoms of the diseases, especially the involuntary resting tremor (Sweeney, 1995). In addition, orphenadrine is a multitarget inhibitor, including N-methyl-D-aspartate (NMDA), muscarinic and histaminic receptors, as well as the norepinephrine reuptake system (Darwish et al., 2012). Orphenadrine was also used as an analgesic either alone or in association with nonsteroidal anti-inflammatory medications (Hunskaar and Donnell, 1991). New evidence showed that there was a decrease in the visual analogue scale (VAS) score between the day of inclusion and before drug infusions of 19% for diclofenac+orphenadrine in chronic low back pain patients on chronic opioid treatment (Wetzel et al., 2014). To date, the detailed molecular mechanism by which orphenadrine induces analgesia is still unknown. The hypothesis of blockade of the voltage-gated sodium channels was acceptable as a strong contributor to the analgesic action of orphenadrine (Desaphy et al., 2009).

Blockade of voltage-gated sodium channels (Desaphy et al., 2009), which are one of the major mechanisms of local anesthesia, produces infiltrative cutaneous analgesia, spinal/epidural anesthesia, and peripheral nerve block (Borgeat and Aguirre, 2010, Vegh et al., 2006). It has been known that orphenadrine with stronger anticholinergic property, a histamine H1 receptor antagonist, is structurally related to diphenhydramine. Diphenhydramine has the local anesthetic properties (Chen et al., 2014, Hung et al., 2011b, Pavlidakey et al., 2009, Suffridge et al., 2009). Because orphenadrine blocked voltage-gated sodium channels, we presumed that orphenadrine may elicit spinal anesthesia.

To the best of our knowledge, no investigation of orphenadrine in spinal anesthesia has been reported to date. The local anesthetics are frequently administered intrathecally for various procedures and pathologies. Spinal anesthesia is a comparatively simple technique, which supports available surgical conditions via the intrathecal injection of a small volume of the local anesthetic with easy landmarks, providing a wide popularity to the practice (Chen et al., 2012b, Vandermeersch et al., 1991). The purpose of our experiment was to estimate spinal anesthesia following intrathecal injections of orphenadrine via assessing motor function, nociception, and proprioception in the rat. Lidocaine, a known local anesthetic, was used as control.

Section snippets

Animals

The experimental protocols were approved via the Institutional Animal Care and Use Committee of National Cheng Kung University (Tainan, Taiwan) and conformed to the recommendations and policies of the International Association for the Study of Pain (IASP). Male Sprague-Dawley rats, each weighing 298–352 g, were purchased from National Cheng Kung University and kept in the animal housing facilities at National Cheng Kung University, with controlled humidity (approximately 50% relative humidity),

The spinal blockade of orphenadrine

Orphenadrine, as well as local anesthetic lidocaine exhibited a dose-dependent local anesthetic effect in spinal anesthesia in rats (Fig. 1A–C). The ED25s, ED50s, and ED75s of drugs are shown in Table 1. On an ED50 basis, the ranks of potencies in motor function, nociception, and proprioception were orphenadrine>lidocaine (P<0.01; Table 1). In addition, orphenadrine, but not lidocaine, produced more sensory/nociceptive blockade (ED50) than motor blockade (P<0.05; Table 1).

The spinal block effect of equipotent orphenadrine and lidocaine

Intrathecal injection

Discussion

In this study we demonstrated that intrathecal orphenadrine produced spinal anesthesia that was more potent than that caused by lidocaine. Orphenadrine, but not lidocaine, elicited greater sensory/nociceptive blockade than motor blockade. At equianesthetic doses, the duration of spinal anesthesia with orphenadrine was greater than that with lidocaine. Coadministration of orphenadrine with lidocaine exhibited an additive effect on spinal anesthesia.

The local anesthetic drugs elicit neural

Acknowledgements

This work was supported by the “National Science Council”, Taiwan (NSC 100-2314-B-039-017-MY3 and NSC 101-2314-B-006-037-MY3).

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