**1.1 History**

*Papaver somniferum L.* is one of the oldest medicinal plants. The first information about the production of opium alkaloids is found on Sumerian clay tablets inscribed


#### **Table 1.**

*The main opium alkaloids found in crude* Papaver somniferum L. *and some information.*

in Cuneiform script in about 3000 BC. The Sumerians, whose culture developed between the Tigris and Euphrates Rivers in the south of Iraq between 4000 and 3000 BC, called the opium alkaloids "Gil" ("happiness") [4].

Opium alkaloids were first isolated in 1803 by Parisian Derosne, and named 'opium salt'. Friedrich Wilhem Adam Serturner described the 'opium salt' in detail in 1817 and named "morphine', inspired by the Morpheus (Greek god of dreams). Karl Friedrich Wilhelm Meissner first used the word 'alkaloid' in 1818, which we still use. Opioids were widely used for the first time in the Franco-Prussian War and the American Civil War for medical purposes. Tincture and pills were preferred for the purpose of analgesia in wounded soldiers. Repeated use caused opioid dependence on some soldiers, and this event was first described as "soldiers' disease" [5].

#### **1.2 Opioid receptors**

Although morphine and other opioid alkaloids are exogenous substances, they show agonistic effect by binding to the receptors of endogenous opioids. Opioid receptors were first described by Beckett and Casy in 1954 [6]. In 1965, Portoghese and colleagues shared their views on the existence of multiple opioid receptor types [7]. High-affinity and stereospecific binding sites for opioid alkaloids were also found in brain in 1973 [8]. The presence of specific opioid receptors led to the discovery of endogenous ligands. They are enkephalins [9], β-endorphin [10], and dynorphins [11]. The classic opioid receptors, were discovered in 1976–1977 and named after the prototypic drugs or tissue used in these studies: μ (mu, for morphine), δ (delta, for deferens), and κ (kappa, for ketocyclazocine) [12, 13]. These receptors show seven transmembrane domain structures specific to G proteincoupled receptors, are induced by morphine and antagonized by naloxone, and had similar analgesic effect. In 1995, the fourth opioid receptor, which is similar in structure with and closely related to classic opioid receptors, was also discovered [14, 15]. Fourth opioid receptor initially identified as ORL1 or LY132, it was later updated to N/OFQ by taking the name of its endogenous ligands (nociceptin/ orphanin FQ) [16]. Although the effects of N/OFQ receptor are not fully known, they do not have a similar effect on pain as classical opioid receptors, and their sensitivity to naloxone is very low. σ (sigma), ε (epsilon), and ζ (zeta) receptors and λ (lambda) site are included in other opioid receptors [17]. The σ receptor, discovered in 1976, is not coupled to G protein, and its effects are not antagonized by naloxone [12, 18, 19]. The ε receptor is sensitive to β-endorphin [20]. The λ site regulates cell growth and is not antagonized by naloxone [21, 22]. Further information on opioid receptors is summarized in **Table 2**.

According to the studies, μ receptor was also related with addiction [38], modulation of dopaminergic system [39], learning and memory [40]. The δ receptors along with μ receptors contribute to emotional sensitivity [41].


**Table 2.** *Opioid receptors and their properties.*
