1.1.	Introduction
In every culture on earth, mind-altering drugs play an important role. Since millennia, man has been using them recreatively and as ingredients of poisonous and healing beverages. The hallucinogens of shamans, arrow poisons of the primal hunters and the curare of South American Indians are the oldest drugs of mankind. Psycho-active plant extracts have been noted to be present in archaic cultures for 12000 years.
The anesthetic and euphoric action of the (opium) poppy was already known by the Sumerians, 6000 years in the past. Even so, until the start of the 19th century, the active ingredients that cause the main effects of opium in all its incarnations was completely unknown. The Paderborn-native pharmacist F.W Serturner isolated and characterized the main active ingredient of opium around 1804. Based on its effects, he named it after the Greek god of sleep Morpheus, morphine. For the treatment of post-operative pain as well as the discomfort caused by tumors, the central nervous depressant opioids are the first choice for analgesia. As effective as they are in pain alleviation, so problematic is the fact that in misguided therapy, dependency can occur. But also unwanted side effects like respiratory depression, bradycardia (low heart rate) and constipation pose a problem for the treatment, so much so that the general condition of the most ill patients on opioids therapy is quite bad. Thus, the search for centrally active analgetics that don’t have these side effects is of continuous importance. It needs to be highlighted that the objective for this search is a conscious organism, that without previous pre-existing pain, is administered the drugs only on the basis of the search of euphoria. People who suffer from pain do not have the same tendency towards dependence and euphoria-seeking behavior development, in comparison to individuals who do not experience pain. Several studies show that even in cancer patients with long-term opioid use, dependency is extremely rare to develop. [translator’s note: this last statement is not true at all imo]].
1.1.	Opioid receptors
A clear step forward in the field of opioid research was the discovery of opioid receptors. The first indication of the presence of not one but multiple opioid receptor types was brought by Martin und Mitarbeitern. Nowadays three distinct receptor types with different subtypes are known. The µ-receptor (named after the most important morphine ligands), the δ-receptor (delta means different) and the κ-receptor, named after the first known ligand, ketocyclazocin.
Further receptor types like ε (epsilon), σ (sigma), λ (lambda), ι (iota) and ζ (zeta) are discussed in literature, although there isn’t much known about these receptors yet, and as such we won’t consider these in this work.
From binding studies, several subtypes of the three opioids receptors are distinguished. Among these are the µ1 and µ2, as well as the δ1 and δ2 opioid receptors. The κ-receptor has 3 subtypes, κ1, κ2 and κ3. However, it is not known yet if these distinct subtypes are also localized in different organs or not.

1.2.	Structure of the receptors and signal transduction

The opioid receptors are part of the G-protein-coupled receptors (Guanin-nucleotid-binding proteins). They are membrane bound proteins and consist of 370-400 amino acids. Further research shows that these receptors consist of seven transmembrane helices, joined together through loops. They contain an extracellular N-terminus and an intracellular C-terminus. Even though these descriptions seem very detailed, it should not be forgotten that at present, only the amino acid sequences of the opioid receptors are known. None of these receptors have been crystallized and analyzed by X-ray crystallography as of yet.

In the past few years, increased efforts have been made to uncover the structure and function of opioid receptors by other methods. The points of departure for these research efforts are mainly mutation and chimeric studies. These build the foundations for literature models of such receptors, that show that by the amino acid sequences and the X-ray structure that the structure of these receptors is similar to the protein rhodopsin, although functionally completely different. Especially for the δ-receptor, in recent times, models have been developed where only the helices are researched, ignoring the ligand binding profiles and signal transduction loops (as evidenced by mutation studies) and environmental effects (lipid flash [tr. Note: no idea what this is], ion channels). Comparing the amino acid sequences of the three opioid rceptors, about 60% of the sequences are identical, with the κ- and δ-receptors showing the highest overlap.

Based on the distinct structure and function of these ligands, they bind to the receptor in different ways. E.g. an extracellular loop of the membrane bound proteins or direct in the binding fold, made by the seven helices. There are conformational changes in the receptor, probably due to phosphorylation at the C-terminus or by the opening of a salt bridge.
This activates an intracellular G-protein, consisting of three subunits (α, β, γ). This leads to the dissociation of guanosindiphosphate (GDP) and the subsequent binding of guanosintriphosphate (GTP), wherein the α-subunit with the GTP dissociates from the βγ-subunit of the G-protein. The α-subunit now binds to an effector protein, e.g. adenylatecyclase or phospholipase C, which regulates the function of several cellular effectors by building semiochemical (signal-transducing) compounds such as AMP (adenosin monophosphate). Through distinct G-protein types, stimulating or inhibiting effects on ion channels, enzymes and transport proteins are exercised. After hydrolysis of GTP to GDP the subunits of the G-protein are welded back together.