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Analgesia Additive Interaction Between Tadalafil and Morphine in Experimental Animal Model

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Analgesia Additive Interaction Between Tadalafil and Morphine in Experimental Animal Model Canadian Journal of Physiology and Pharmacology Analgesia Additive Interaction between Tadalafil and Morphine in Experimental Animal Model Journal: Canadian Journal of Physiology and Pharmacology Manuscript ID cjpp-2019-0674.R2 Manuscript Type: Article Date Submitted by the 24-Apr-2020 Author: Complete List of Authors: Mehanna, Mohammed; Beirut Arab University, Pharmaceutical technology Domiati, Souraya ; Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon, Nakkash Chmaisse,Draft Hania ; Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon, El Mallah, Ahmed ; Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt Is the invited manuscript for consideration in a Special Not applicable (regular submission) Issue: Keyword: Morphine, Antinociception, Isobolographic analysis, Nitric oxide, Tadalafil https://mc06.manuscriptcentral.com/cjpp-pubs Page 1 of 20 Canadian Journal of Physiology and Pharmacology 1 Analgesia Additive Interaction between Tadalafil and Morphine in Experimental 2 Animal Model 3 Mohammed Mehanna1*, PhD, Souraya Domiati2, Pharm D, MSc, PhD; Hania Nakkash Chmaisse3, PhD; 4 Ahmed El Mallah4, PhD; 5 6 1Department of Pharmaceutical technology, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon, 7 [email protected] 8 2Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon, 9 [email protected] 10 3Department of Pharmacology and Therapeutics, Faculty of Pharmacy, Beirut Arab University, Beirut, Lebanon, 11 [email protected] 12 4Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt, 13 [email protected] 14 15 16 17 18 19 20 *correspondent email: [email protected]; Beirut Arab University, Beirut Campus, Tarik El Jadida; Phone 21 number 96101300110 ext. 2867; P.O. Box 11-5020 Riad El Solh 11072809- Beirut, Lebanon 22 23 1 https://mc06.manuscriptcentral.com/cjpp-pubs Canadian Journal of Physiology and Pharmacology Page 2 of 20 24 Abstract: 25 Since both morphine and tadalafil have been proven to exert some of their analgesic activity 26 through modulation of the NO-cGMP pathway, the aim of the current study is to evaluate the 27 pharmacologic interaction between tadalafil and morphine in order to decrease the dose of 28 morphine and subsequently its side effects. The assessment was carried out through isobolographic 29 analysis relative to ED50s of both morphine and tadalafil obtained by tail-flick test on BALB/c 30 mice. Morphine and tadalafil ED50s calculated from the dose-response curves were 8303 µg/kg 31 and 2080 µ/kg, respectively. The experimental ED50 values of morphine and tadalafil in their 32 mixture were 4800 µ/kg and 1210 µ/kg, respectively. Those results showed an additive interaction 33 between morphine and tadalafil presentedDraft by a total fraction value for the mixture of 1160 µ/kg. 34 This outcome can be interpreted by the fact that both drugs share common pathways namely, NO- 35 cGMP and opioid receptors. As a conclusion, morphine and tadalafil combination showed an 36 additive effect against acute pain, which is mediated through the central nervous system, thus 37 providing a rationale for combining them in order to decrease morphine dose and thus minimizing 38 its side effect. 39 40 Keywords: Antinociception, analgesia, Drug-interaction, Isobolographic analysis, Morphine, 41 Nitric oxide, Phosphodiesterase 5 inhibitor, Tadalafil. 42 43 44 45 2 https://mc06.manuscriptcentral.com/cjpp-pubs Page 3 of 20 Canadian Journal of Physiology and Pharmacology 46 1. Introduction 47 Nitric oxide (NO) is produced in different cell types through the action of specific neuronal and 48 non-neuronal nitric oxide synthases on L-arginine, as a substrate. NO plays a major role in diverse 49 physiologic functions relevant to white blood cells, blood vessels, and the central nervous system 50 via targeting the cytosolic enzyme soluble guanylyl cyclase which converts guanosine -5’ 51 triphosphate (GTP) into the second messenger cyclic guanosine monophosphate (cGMP). The 52 latter has many cellular targets among which cGMP-dependent protein kinases and cyclic 53 nucleotide-gated ion channels control up/down nociceptors expressions. cGMP is further degraded 54 by the specific phosphodiesterases 5, 6 and 9 to GMP which terminates the signal transduction 55 (Florentino, Galdino et al. 2015, Florentino,Draft Silva et al. 2017). In fact, the complex role of NO- 56 cGMP system in the modulation of nociception has been proven in both acute and chronic pain on 57 central and peripheral levels (Ambriz-Tututi, Velazquez-Zamora et al. 2005, Gediz, Nacitarhan et 58 al. 2015). NO formation is induced and terminated within few seconds after reacting with its 59 intracellular targets (Sharma, Al-Omran et al. 2007). Therefore, the cornerstone of pain 60 management is NO biosynthesis modulation and cGMP formation. Accordingly, different 61 phosphodiesterase inhibitors have been investigated for their analgesic effect. Sildenafil, tadalafil, 62 vardenafil, and other phosphodiesterase inhibitors, used in the treatment of erectile dysfunction, 63 have been proven to exert an antinociceptive effect in different pain models (Ambriz-Tututi, 64 Velazquez-Zamora et al. 2005, Rocha, Silva et al. 2011, Pasternak 2014). In fact, according to 65 Rocha, Silva et al.(2011), tadalafil antinociceptive effect was due to inhibition of neutrophil influx 66 and tumor necrosis factor alpha release in an inflammatory pain model in rat. NO was proven by 67 Otari and Upasani (2015) to play an essential role in in tadalafil analgesic effect in carrageenan 3 https://mc06.manuscriptcentral.com/cjpp-pubs Canadian Journal of Physiology and Pharmacology Page 4 of 20 68 pain model. Furthermore, Mehanna et al (2018) demonstrated that tadalafil analgesic effect 69 involved several receptors and mediators at the central and peripheral pain pathways. 70 Morphine, a well-defined analgesic, exerts its action mainly on mu as well as delta and kappa 71 opioid receptors (Pasternak 2014). In 1997, Granados-Soto et al. proved that morphine peripheral 72 analgesia is associated with the activation of L-arginine-NO-cGMP pathway (Granados-Soto, 73 Rufino et al. 1997). Moreover, several studies have shown that morphine induces nitric oxide 74 synthase formation thus leading to the elevation of nitric oxide concentration at the supraspinal 75 level, which in turn contributes to opioid-suppression of perception of pain signals in the higher 76 centers (Granados-Soto, Rufino et al. 1997, Basbaum, Bautista et al. 2009, Ghelardini, Di Cesare 77 Mannelli et al. 2015). In fact, opioid analgesic effect was demonstrated by conditional gene 78 knockout approaches to involve supraspinal,Draft spinal, and peripheral actions (Sawynok & Liu 2014). 79 Although morphine is a potent analgesic agent, it should be used with caution as it can induce 80 several side effects ranging from nausea, vomiting, pruritus, sedation up to respiratory depression 81 and death, especially at high doses. Moreover, long term use of morphine can lead to tolerance and 82 physical addiction (Dumas and Pollack 2008, Hong, Flood et al. 2008). As a consequence, in order 83 to decrease the dose of morphine and accordingly its side effects, several studies have investigated 84 the beneficial pharmacologic interaction of morphine with different drugs such as sildenafil and 85 zaprinast, two phosphodiesterase 5 inhibitors. In fact, additive antinociception was proven between 86 sildenafil and morphine while synergistic antinociception was demonstrated between zaprinast and 87 morphine (Yoon, Choi et al. 2006, Yoon, Park et al. 2008, Chen, Ma et al. 2010). 88 In light of the aforementioned facts, the aim of the current study is to investigate and evaluate the 89 potential possible interaction between tadalafil and morphine with respect to their analgesic 90 effects. 91 4 https://mc06.manuscriptcentral.com/cjpp-pubs Page 5 of 20 Canadian Journal of Physiology and Pharmacology 92 2. Material and methods 93 2.1 Animals 94 Animal handling and experimental procedures were performed in accordance with the regulations 95 and guidelines stipulated by the Institutional Animal Care and Use Guidelines (IACUG) at Beirut 96 Arab University, Lebanon (IRB number 2016A-0043-P-P-0165) as well as the Canadian Council 97 on Animal Care (CCAC). Male BALB/c mice (20-25g), housed in polyacrylic cages under 98 standard conditions, were used. Animals had free access to water and standard laboratory chow. 99 2.2 Chemicals and drugs 100 Tadalafil and morphine sulfate (15mg/ml) used in the experimental work were obtained from 101 Pfizer and Renaudin, respectively. TadalafilDraft and morphine were dissolved in polyethylene glycol 102 400 (Fluka analytica) and normal saline, correspondingly to be administered intraperitoneally. 103 2.3 Apparatus for pain assessment 104 A tail flick analgesic apparatus type 812, Ugo Basile®, Germany was used in addition to a 105 plexiglass restrainer. 106 2.4 Experimental procedure 107 Tail flick test was used to study the nociceptive effect of tadalafil, morphine and their combinations 108 in addition to determine their ED50 (Bannon and Malmberg 2007). A total of 105 mice were used. 109 To determine the most suitable time latency for the isobolographic analysis, two different doses of 110 tadalafil (1 and 1.5 mg/kg) and two doses of morphine (2.5 and 5mg/kg) were administered
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