Does Nicotine Impact Tramadol Abuse? Insights from Neurochemical and T Neurobehavioral Changes in Mice
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Neurotoxicology 67 (2018) 245–258 Contents lists available at ScienceDirect Neurotoxicology journal homepage: www.elsevier.com/locate/neuro Full Length Article Does nicotine impact tramadol abuse? Insights from neurochemical and T neurobehavioral changes in mice Shimaa M. Azmya, Mai A. Abd El fattahb, Sahar S. Abd El-Rahmanc, Somia A. Nadad, ⁎ Omar M.E. Abdel Salame, Mohammed F. El-Yamanyb, Noha N. Nassarb, a Analytical Toxicology Laboratory, Forensic Medicine Authority, Cairo, Egypt b Pharmacology and Toxicology Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt c Pathology Department, Faculty of Veterinary Medicine, Cairo University, Egypt d Pharmacology Department, National Research Center, Giza, Egypt e Toxicology and Narcotics Department, National Research Center, Giza, Egypt ARTICLE INFO ABSTRACT Keywords: Nicotine and tramadol concomitant drug dependence pose increasing social, economic as well as public threats. Nicotine Accordingly, the present study investigated neurochemical, neurobehavioral and neuropathological changes in Tramadol the brain subsequent to the interaction of nicotine and tramadol. To this end, tramadol (20 mg/kg, i.p) and Dopamine nicotine (0.25 mg/kg, i.p) were administrated to male albino mice once daily for 30 days. Consequent to mi- Dependence croglial activation, nicotine exacerbated oxidative/nitrosative stress induced by tramadol as manifest by the Memory step-up in thiobarbituric acid reactive substances and nitric oxide subsequent to the enhanced levels of neuronal Anxiety and inducible nitric oxide synthases; paralleled by decreased non-protein sulfhydryls. Increased oxidative stress by tramadol and/or nicotine sequentially augmented nuclear factor kappa B and the proinflammatory cytokine tumor necrosis factor α with the induction of apoptosis evident by the increased caspase-3 immunoreactivity. However, paradoxical to the boosted inflammation and apoptosis, heightened DA levels in the cortex parallel along with increased tyrosine hydroxylase in midbrain were apparent. Concomitant administration of tramadol and nicotine impaired spatial navigation in the Morris Water Maze test coupled with enhanced levels of acetyl- and butyryl cholinestrases. However, tramadol in association with nicotine improved social interaction while decreasing anxiety and aggression linked to chronic administration of nicotine, effects manifested by increased levels of serotonin and GABA. These results provide evidence that co-administration of tramadol and nicotine may enhance reward and dependence while reducing anxiety and aggression linked to nicotine administration. However, such combination exacerbated neurotoxic effects and elicited negative effects regarding learning and memory. 1. Introduction (Frosch et al., 2000; Elkader et al., 2009; Epstein et al., 2010). Tramadol, a centrally acting synthetic opioid, that possesses anti- Drug addiction, including polydrug use, can be defined as a mala- nociceptive and analgesic effects (Raffa, 2008) has emerged rapidly as a daptive behavior which is characterized by “loss of control "over drug drug of abuse in the past few years (Shalaby et al., 2015). It has been use (Balconi et al., 2014). The diversity and abuse of prescription drugs, postulated that the pharmacological effects of tramadol may be medi- particularly opioids is a major worldwide tendency (Simonsen et al., ated by both opioid (μ-receptor agonist) and non-opioid (nor- 2015). Nonetheless, concomitant drug dependence is not only limited epinephrine and serotonin reuptake inhibition) mechanisms (Raffa to prescription medications but also encompasses nicotine and opioids. et al., 1992; Liu et al., 1999; Nossaman et al., 2010), with the in- In this context, some epidemiological studies revealed that tobacco volvement of both in development of drug addiction (Zhuo et al., 2012). smoking and illicit drug use are frequently a co-occurring behavior Noteworthy, tramadol metabolite, o-desmethyl tramadol (M1), is also Abbreviations: AChE, acetylcholinesterase; BuChE, butyrylcholinesterase; GABA, gamma aminobutyric acid; GLU, Glutamate; GSH, reduced glutathione; iNOS, Inducible nitric oxide synthase; LLE, liquid liquid extraction; M1, O-desmethyl tramadol; MWM, morris water maze; NFκB, nuclear factor kappa B; NMDA, n-methyl-D-aspartate; nNOS, neuronal nitric oxide synthase; NO, nitric oxide; NOS, nitric oxide synthase; NPSH, non protein sulfhydryl; OFT, open field test; RNS, reactive nitrosative species; ROS, reactive oxygen species; SI, social interaction; TBARS, thiobarbituric acid reactive substances; TH, tyrosine hydroxylase; TNF-α, tumor necrosis factor alpha; VTA, ventral tegmental area ⁎ Corresponding author. E-mail address: [email protected] (N.N. Nassar). https://doi.org/10.1016/j.neuro.2018.06.004 Received 12 December 2017; Received in revised form 16 May 2018; Accepted 10 June 2018 Available online 12 June 2018 0161-813X/ © 2018 Published by Elsevier B.V. S.M. Azmy et al. Neurotoxicology 67 (2018) 245–258 active as μ-receptor agonist, such that the long-term use of tramadol can throughout the last week of the experiment while body weight was induce tolerance, physical dependence and withdrawal symptoms taken on weekly basis. Following the exclusion of dead animals in each (Abdel-Zaher et al., 2011). Addicts may revert to tramadol combina- group, the experimental groups I and III consisted of (6–8 animals) tions with other substances of abuse either to increase euphoria, whereas groups II and IV included (12–14 animals). Thirty minutes achieve more favorable effects, act as a substitute or avoid/relieve the following last tramadol injection in groups II and IV, (4–6 mice) were opioid-related withdrawal symptoms (Gibson, 1996; Liu et al., 1999); euthanized and the brains were isolated for detection of tramadol in however, these practices have augmented the number of deaths in re- brain. Twenty-four hours following the last treatment, (6–8 mice each cent years (Sheikholeslami et al., 2016). group) were euthanized with cervical dislocation and brains were iso- Tobacco consumption is one of the main public health problems lated. Cortices were dissected over ice for neurotransmitters and bio- worldwide and represents a leading cause of preventable deaths in most chemical analysis. Part of cortical tissue was homogenized in 75% developed countries (Dwoskin et al., 2009; Berrendero et al., 2010). methanol (HPLC grade, Sigma-Aldrich) and cortical monoamines were Nicotine, the reinforcing addictive component of tobacco, is the major measured. Derivatization of dried cortical homogenate was carried out arbitrator that maintains the smoking habit (Shoaib, 2006). Like other for determination of GABA and glutamate. The rest of cortical tissue addictive drugs, nicotine displays the two important characteristics to was homogenized in phosphate buffer saline (pH 7.4) for estimation of establishing and maintaining addiction; first, by eliciting pleasant or other mediators in cortices. Samples were stored at −80 °C till analysis. rewarding effects in the brain which reinforce self-administration be- havior; and secondly, appearance of withdrawal syndrome following 2.4. Detection of tramadol in brain chronic exposure to nicotine which favors continued intake (Lewis et al., 2007). Thirty minutes following the last injection, mice were euthanized Neurochemical studies revealed that nicotine and opioids modulate with cervical dislocation and brains were isolated and homogenized in each other effect (Skurtveit et al., 2010) and nicotine induced DA re- Tris−HCl buffer. Extraction of tramadol from brain homogenates was lease via activation of μ opioid receptors (Tanda and Di Chiara, 1998). performed according to the method described by Tao et al. (2001). Moreover, experimental studies highlighted the existence for a me- Briefly, methanol was used for protein precipitation and methyl tertiary chanistic overlap between opiates and nicotine within dopamine (DA) butyl ether (MTBE) was utilized for liquid-liquid extraction (LLE). reward pathway (Britt and McGehee, 2008; Berrendero et al., 2010). In Subsequently, the MTBE layer was evaporated under nitrogen flow and light of these considerations, the aim of this work was to investigate the the residue was reconstituted with 50 μl of methanol (HPLC grade). A possible modulatory effects of nicotine on tramadol-induced neurobe- sample volume of 3 μl was injected in GC.MS (Agilent 6890 Network havioral and neuropathological changes in the brain. In addition, an capillary gas chromatograph equipped with a mass selective detector attempt was undertaken to clarify the possible neurochemical altera- Agilent 5973 Network; CA, USA) using dextromethorphan as internal tions in neurotransmitters, inflammation and oxidative/nitrosative standard (I.S.). stress. 2.5. Biochemical measurements 2. Material and methods 2.5.1. Determination of cortical TBARS, NPSHs and NO contents 2.1. Animals Thiobarbituric acid reactive substances (TBARS) content was mea- sured according to the method described by Mihara and Uchiyama Adult male Swiss albino mice weighing 25–30 g were purchased (1978). In brief, thiobarbituric acid in o-phosphoric acid was added to from the animal house colony of the national research center (NRC, the homogenate and boiled for 20 min, cooled and centrifuged at 1000 g Giza, Egypt). Mice were allowed one week acclimatization period and for 10 min then the resultant complex was read at 532 nm. Non protein were housed in groups at constant temperature (23 ± 2 °C), humidity sulfhydryls