Neuropharmacology and analgesiaIntrathecal orphenadrine elicits spinal block in the rat
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.
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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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2015, European Journal of PharmacologyCitation Excerpt :The curves were then fitted by using SAS Nonlinear Procedures (version 9.1; SAS Institute, Cary, NC), and the value of ED50, which defined as the dose that elicited 50% cutaneous analgesia, was obtained (Chen et al., 2012a; Leung et al., 2013b; Minkin and Kundhal, 1999). The ED25 or ED75 was calculated by using the same curve-fitting (SAS NLIN Procedures) system, which was used to derive the ED50 (Chen et al., 2011, 2014b). The values of AUCs of nociceptive/sensory block were calculated by using the Kinetica version 2.0.1 software (InnaPhase Corporation, Philadelphia, PA).
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2015, European Journal of PharmacologyCitation Excerpt :It has been known to be widely used as an anti-histamine drug for both animals (Kuroda et al., 2013; Sankar et al., 1974) and humans (Moreno et al., 2010; Peets et al., 1972) and is an important mediator of various allergic diseases for 50 years (Kuroda et al., 2013). There is a growing body of evidences that several H1-antihistamines have the local anesthetic effects (Chen et al., 2014a, 2014c; Hung et al., 2011; Mattern and Gander, 1968; Pavlidakey et al., 2009; Stubbart, 1953). Moreover, the first generation H1-receptor antihistamine (i.e., diphenhydramine) may be a safe, alternative local anesthetic in patients who confirm with a history of “allergies“ to local anesthetics (Pavlidakey et al., 2009; Suffridge et al., 2009).
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Contributed equally to this work.