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    • Obesity is one of the worldwide concerns with high

    2021-10-15

    Obesity is one of the worldwide concerns, with high prevalence and adverse effects on human health and life expectancy. According to the World Health Organization (WHO), obesity is defined as abnormal or excessive fat accumulation in the body with body mass index (BMI) of 30 or more. Obesity increases the risk of serious health problems such as cardiovascular disease, cancer, diabetes type 2, and obstructive sleep 891 (Berlin et al., 2011; Leurs et al., 2005; Passani, Blandina, & Torrealba, 2011; Sander et al., 2008). Metabolic homeostasis establishes a balance between food intake and energy expenditure through a large number of pathways in the body. Appetite and satiety are two critical components of eating behavior, which is regulated by a large number of orexigenic and anorexigenic signaling pathways in the central and peripheral nervous systems (Berlin et al., 2011; Lee et al., 2008; Passani et al., 2011; Sandoval, Cota, & Seeley, 2008). Several investigations reflect the paramount role of neuronal histamine in feeding behavior mediated by central H3 and H1 receptors. Loss of appetite and reduced body weight have been observed in response to elevated hypothalamic histamine levels in rodent models following the blockade of H3 autoreceptors (Leurs et al., 2005; Passani et al., 2011; Plancher, 2011; Singh & Jadhav, 2013). Interestingly, the other side of the histamine action on modulating the eating behavior occurs through central H1 receptors, whose stimulation suppresses food intake and leads to weight loss in rodents. This is the main reason behind the growing interest in developing H3R antagonists as anti-obesity therapeutic agents. However, there is a controversy about the exact mechanism of H3R involvement in the feeding process as few reports indicate H3R-induced anorexia in animal models (Berlin et al., 2011; Passani et al., 2011; Schlicker & Kathmann, 2017) and conflicting observations also described reduced food-intake in mice followed by H3R activation with imetit as agonist (Yoshimoto et al., 2006). More clarification in this area is therefore needed. Drug addiction is a compulsive multifaceted behavior which is characterized by continuous consumption of drugs in an out of control manner. Although it is believed that mesolimbic dopaminergic system underlies in dopamine hypothesis of drug addiction, the role of histaminergic system on psychomotor and rewarding effects of addictive drugs should not be ignored (Brabant, Alleva, Quertemont, & Tirelli, 2010; Ellenbroek & Ghiabi, 2014; Vohora & Bhowmik, 2012). Studies have demonstrated that dopamine transmission can be reduced by histamine via presynaptic and postsynaptic H3R located on dopaminergic and GABAergic neurons in striatum (C. Brabant et al., 2010; Vohora & Bhowmik, 2012). There are some lines of evidence indicating the effectiveness of H3R antagonist/inverse agonists in alcohol abuse in animal models in preclinical studies (Galici et al., 2011; Nuutinen et al., 2016; Nuutinen, Vanhanen, Maki, & Panula, 2012; Rezvani, Lawrence, Arolfo, Levin, & Overstreet, 2012; Vanhanen et al., 2013). It has been observed that direct antagonizing of dopamine receptors is associated with some limitations including inefficacy and adverse effects, therefore, H3R antagonist/inverse agonists can be potential alternative agents in drug abuse. As an inflammatory mediator, histamine plays a pivotal role in nociceptive processes in both the central and peripheral nervous systems (Gemkow et al., 2009; Hough & Rice, 2011; Tiligada et al., 2009). In this respect, the participation of H3Rs in modulating pain, especially neuropathic pain, has attracted attention for the design of H3R-related therapeutic agents, although the function of H3R agonists and antagonists as pain relievers remains a debatable issue and maybe attributable to side-target effects such as sigma-1 receptor antagonism (Berlin et al., 2011; Riddy et al., 2019; Sander et al., 2008; Wijtmans, Leurs, & de Esch, 2007). The available information reveals a paradoxical effect for peripheral and central histamine. Peripheral histamine triggers the stimulation of nociceptive fibers present in the skin and spinal cord, whereas central histamine reduces the transmission of nociception in the brain. There are several reports demonstrating the antinociceptive effect of H3R antagonists originated from augmented release of neuronal histamine (Hough & Rice, 2011). In contrast, inconsistent effects have been observed for H3R agonists (Berlin et al., 2011; Wijtmans et al., 2007). It seems that different animal pain models and administration routes considerably affect the biological response for given H3R agonists/antagonists. But H3R antagonists appear more beneficial in terms of antinociceptive activity and can be promising agents for the treatment of different kinds of pain, in particular neuropathic pain (Berlin et al., 2011; Gemkow et al., 2009).