## 1 Introduction  
Imidazoline receptors (IR) were initially described as a family of non-adrenergic binding sites with affinity for compounds containing an imidazoline moiety; however, this definition has proven reductive, as none of the proposed endogenous ligands possess such a structural motif, and their chemical diversity suggests a broader pharmacological profile. Three subtypes, designated II, I2, and I3, have been proposed, each with varying degrees of molecular and functional characterization, reflecting the complex and evolving understanding of this receptor family. I1 receptors contribute to the central hypotensive effects of clonidine-like drugs, and newer agents such as maxonidine, rilmenidine, and LNP599 offer improved therapeutic profiles through greater selectivity, with potential applications in the treatment of hypertension and metabolic syndrome. I2 receptors, although not yet fully defined at the molecular level, are associated with central effects such as antinociception and neuroprotection; notably, the I2 agonist CR4056 has shown promising analgesic activity in phase II clinical trials, positioning it as a potential first-in-class non-opioid analgesic. In contrast, I3 receptors are the least understood but may modulate insulin secretion via ATP-sensitive potassium channels in pancreatic \(\beta\)-cells. Despite the incomplete characterization of their molecular targets, IR, particularly II and I2 (Figure 1), represent a promising focus for drug development aimed at managing hypertension, metabolic disorders, and chronic pain [1]. The components of the imidazoline system play pivotal roles in various physiological functions, particularly within the central nervous system (CNS) [1]. IR exerts its influence across normal states and diverse diseases, as well as analgesia, tolerance, and dependence [2; 3]. Among the drugs that work with these receptors, tramadol is notable because it acts on the central nervous system to relieve pain and has both opioid and non-opioid effects [4]. Tramadol (trans-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol hydrochloride) is a centrally acting analgesic with opioid and non-opioid actions [5]. Tramadol (Figure 2) is a synthetic substance, a 4-phenyl-piperidine analogue of codeine, and also a racemic mixture of two enantiomers [6]. These two have different affinities for \(\mu\) receptors and elicit different actions. The + enantiomer is a \(\mu\) receptor agonist and strongly inhibits serotonin reuptake, while -tramadol inhibits noradrenaline reuptake. The action is synergistic, and both contribute to the analgesic effect of this drug [7]. Tramadol, widely recognized for its effective analgesic properties coupled with a lower potential for addiction relative to traditional opioids, has attracted considerable clinical and research interest. It is characterized by a synergistic effect with other drugs used in the treatment of chronic pain, such as acetaminophen and gabapentin [8; 9]. Another synergistic association is tramadol + equricoxib against mechanical hyperalgesia of spinal cord injury [10]. Tramadol pretreatment is also known to enhance ketamine-induced antidepressant effects [11]. Recent studies have shed light on its complex interaction with the  
Figure 1: I1 receptor antagonists (**left**) and I2 receptor antagonists (**right**). brain's reward circuitry, revealing significant modulation of key neuroanatomical regions, including the locus coeeruleus, amygdala, hippocampus, ventral tegmental area, prefrontal cortex, basal ganglia, and nucleus accumbens [12; 13]. These findings underscore the multifaceted mechanism of action and its influence on both pain perception and neurobehavioral pathways associated with reward and dependence [14; 15]. Furthermore, it is known that after oral administration, tramadol's bioavailability is 68%, and the maximum serum concentration is reached within 2 h, with the half-life situated at 5.1 h. Tamadol is metabolized by cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4 [16].