2. Historical Outline

Pain has been known since the dawn of time, for as long as living organisms have existed. Considered as a complex physiological phenomenon, pain provides evidence of the effective impact of the external and internal environment on organisms. Pain is regarded as a special type of experience that results in various affective reactions with strong emotional components. As far back as 1550 BCE, opium was used to relieve pain and was described on Ebers papyrus. Hippocrates (460–377 BC), named by posterity the father of medicine, claimed that pain is one of the actual symptoms of disease. According to him, the brain was the main location of pain sensation; therefore, it is not surprising that, for many centuries, pain was considered to be a symptom of disease of the soul and heart. Galen (130–201) and Avicenna (980–1037) were pioneers in identifying the location and causes of pain formation, claiming that the phenomenon of pain develops in the brain and nerves because of sudden shifts in the distribution of body fluids and changes in tissue continuity. Leonardo da Vinci (1442–1519) presented a still valid hypothesis that pain was associated with touch sensation, being a consequence of an excessive stimulus action, currently termed a noxious stimulus. Descartes (1569–1650) presented in his work “Tractatus de homine”, a description of a hypothetical path through which impulses pass from the site of action to a center in the brain. It was not until the 20th century that a breakthrough in research occurred concerning on pain perception. The results of experimental studies carried out in the last two decades have provided biological evidence for progress in the recognition of both the morphological and the functional basis of the phenomenon of pain perception. However, controversies and inconsistencies of this fascinating phenomenon are still evident. In particular, in recent years, other endogenous opioids, termed endogenous morphines (endomorphin-1, endomorphin-2), were discovered ^[3][4][5] and the presence and structure of a presumed endogenous pain transmitter (nociceptin) was reported, but the transmitter’s biological role in living organisms is still being elucidated ^[6][7].

Since the time of Sertürner, who, in 1804, isolated the substance he named after the god of sleep, Morpheus, it is known that the compound that reduces or abolishes the adverse effects of pain stimuli is morphine, a phenanthrene opium alkaloid from Papaver somniferum with analgesic and narcotic effects (addictive and tolerance-inducing). Fifty years after its isolation, morphine was added to the arsenal of drugs used in the treatment of postoperative and chronic pain ^[8].

Alleviation of endogenous pain by an exogenous alkaloid brought up an assumption that a morphine-specific locus of action must exist in living organisms. Over time, the presence of receptors for morphine, later named opioid receptors, was validated, and other receptors were subsequently identified, named, and localized. The existence of three basic groups of opioid receptors (µ, δ, and κ) was determined, and the division into subtypes of these groups (µ₁, µ₂, δ₁, δ₂, κ₁, κ₂, and κ₃) was suggested by some authors (Table 1). These receptors are distributed over the central and peripheral nervous system and organs (Table 2) and are present at the highest density in the structures responsible for reception and conductivity of pain stimuli in humans and other vertebrates ^[3][4][7]. Furthermore, the presence of various opioid receptors in the organism’s structures suggested the existence of endogenous substances specific for these receptors. The existence of compounds with morphine-like activity was, thus, proven and named endogenous morphine (endorphins), which are peptides with opioid activity (endogenous opioid peptides; EOPs) (Figure 1). To distinguish endorphins from opioid-like substances of exogenous origin, exogenous substances were named opiates. Subsequently, numerous endorphins were identified in the body (Figure 1) ^[4][6].

Figure 1. Structure of endogenous opioid peptides (EOPs) ^[1].

In the wake of the achievements of theoretical sciences, exogenous substances that mimic the effects of endogenous endorphins were soon developed. Some of the obtained opiate substances proved to be 1000–80,000 times more potent in analgesic tests than their protoplast, morphine ^[1][10]. However, these substances have certain adverse effects in some species, particularly ruminants ^[1][11]. Effects are excitant and sympathomimetic, and, in humans, there is stimulation of the reward system (addiction) and inducement of tolerance to these drugs. Differences are due to the fact that companion animals have well-developed analgesic and preanesthetic processes ^[8][11] and farm animals suffer from a constant deficiency of these processes ^[12][13].

Non-narcotic analgesics for suitability for use in ruminant anesthesiology (α₂-adrenergic receptor agonists, nonsteroidal anti-inflammatory drugs (NSAIDs) ^[8], local anesthetics, ionotropic glutaminergic receptor antagonists (iGluRAs) such as ketamine, and voltage-gated calcium channel inhibitors (VGCCIs; diltiazem, nifedipine, verapamil, type 1 cholecsystokinin receptor antagonists—CCK₁)) have been the subject of recent research interests. Sheep, for example, have many behavioral and biochemical reactions that are similar to human reactions ^[13]. This was a main reason for undertaking this study to investigate a new method for determining visceral pain during the viscero-visceral inhibitory reflex test in use since the 1990s ^[14].