Theories of pain, up to Descartes and after neuromatrix: what role do they have to develop future paradigms?

The article represents a synthesis of literature about antique, medieval and modern pain theories. In short there are described the most relevant theories about nociception and pain. Chronologically there are presented the discoveries in physiology, anatomy, histology and other methods and investigations of pain. There is discussed the character of past pain theories and its influence on elaboration of the new ones. There was elaborated the hypothesis about the neuromatrix theory and impact of human microbiota on pain perception or other comorbidities with psychological and pain component.


Introduction
Periodically, in the scientific medical journals are published articles on the history of medicine, including in the field of pain. The result of working in the archives of medical history of the enthusiasts, is already synthesized, integrated and accessible today, to practically everyone. Although it is impressive, viewed from a historical perspective, the amount of knowledge held is somewhat constant, finite as available information, in particular, relative to the scale of today's information age.
Consequently, most authors give the same data, depending on the possibility of access to archives or the degree of documentation in the field, data, that are seen from one point of view or another. Thus, traditionally, there are presented the ancient and medieval theories (up to Descartes), philosophical of pain, which reflect the thinking, culture and conceptions of the world of the civilization of that time [1,2,3].
The modern age is reflected in the structural and functional theories of pain, starting from nociceptor and reaching the central nervous system. Typically, they describe the microscopic level of structures, which at this level maintain certain functions (potentials of action, coded by intensity and frequency or centrifuge axiomatic biochemical flow) [1][2][3]7].
The theories and contemporary models of pain (control gate theory, neuromatrix theory, multidimensional model of pain etc.) hold the full conceptual power at present. And these theories are based on structures and functions, which, however, in the light of today's technology, are viewed, described and explained on a submolecular, informational or oversized interaction scale.
Undoubtedly, sooner or later, these theories and patterns will be updated with new ones...
In view of the above, I propose, however, an article of history of pain theories... Why another article on pain theories? I consider, that new generations of specialists in trening, would be useful to review the evolution of pain theories over the centuries. These theories, in their time, were the basis for the development of pain-fighting methods and techniques, the pharmacological industry with analgesics, institutional and national organizational measures to fight pain. The new theories of pain go beyond the pure pharmacological and physical approach to pain, requiring a biopsychosocial, multidimensional and interdisciplinary approach. I intend not break the "traditions" of displaying history articles, but up to a certain point. After that, I will try, based on "history", to formulate a hypothesis of a (future?) pain theory: what beyound neuromatrix? Because, "Progress is not an accident, but a necessity… It is a part of nature". (Herbert Spencer , Social Statistics).

Pain Theories up to Descartes
The ancient theories of pain reflected the philosophical ideas of time about life, existence, perception of the world, based on empirical reflections. Their essence is presented in Table 1.
The main questions about pain, have remained unresolved for centuries: pain appears as a result of the activity of a dedicated neural device or is the product of a less specific process?

Modern age: from specificity of structures and functions to gate control theory
Until the second century. XIX, it was thought that the senses depend on the transport of some substance out of the brain or heart.
Century. XIX has been characterized by the co-existence of three concepts: (1) pain is an emotion (the ancient philosophers and the psychologists of the times); (2) pain is a sensation, with sense organs and own transmissions (Avicenna, Schiff); (3) Intense stimulation of other related systems that serve other sensations generates pain over a certain threshold (Erb, psychologists, doctors).
One of the arguments, against the theory of pain specificity, was that pain can also be produced by mechanical, thermal or chemical stimuli, which are different in terms of the receptive structure and the nociceptive pathway. The polemics in the "specificity theory" continued until the 1970s, XX century.
The most important findings on nociception and pain between 1911 and 2003 years, are listed in Table 2. Approx.

Hippocrates of Kos
Pain comes from the body fluids. The heart is the main organ of pain perception ( Fig. 1)

Platon
Pain, as well as pleasure, is a passion for the soul

Aristoteles
Evil spirits penetrate the body through various injuries. The heart is the center of the senses. He did not consider pain as a special sense, but was an emotion

Galen
The brain is the organ of the senses, and the pain was placed in the sphere of sensations

Theories of specificity
The essence of the theory lies in the fact that each somato-sensorial mode (somatosensorial modality) is dedicated to a specific way of transmission. A specific receptor that is sensitive to a particular stimulus is connected to a primary sensory nerve fiber. For example, mechanical stimuli are detected by low threshold mech-

Hippocrates and Galen believed that all the illnesses came from the four fluids of the body: the phlegm, the yellow ball, the black ball and the blood. The flow and reflux of each of the fluids is a response to changes in the body or the environment. Pain is caused by increased blood viscosity, which stops flowing from each narrow passage in its path
anoreceptors, and the primary sensory nerve fiber transmits the impulse to the second neuron, and it is "mechanoreceptive", in the spinal cord or the cerebral trunk. The secondary "mechanoreceptive" neurons, in turn, project to the cortical structural receptors. Similarly, noxious stimuli will be projected to "higher pain centers" through nociceptive fibers (Dubner et al., 1976). Describe the complexity of the peripheral nerve potential and its relationship to the diameter of the nerve fiber. Nerve fibers with different driving speed are involved in pain Gate control theory Proposed in 1965 by Ronald Melzack and Patrick Wall, the theory provides a physiological explanation of the findings made in the psychology of pain perception. She "reconciled" the theories of specificity and patterns, revolutionized research into nociception and pain.
The essence of the theory is that the painless impulses transmitted through thicker, myelinated (Aβ) fibers will close the "gate" of painful impulses (transmitted through the myelinated Aδ and unmyelinated fibers, type C), thus preventing them from reaching the central nervous system. Inhibition is presynaptic and involves interneurons in the structure (Fig. 2). Although the conceptual structure of the neural circuit is simple schematized, it is much more complex, both as a network and biochemical composition.

Contemporary theories
The theory of neuromatrix According to Ronald Melzack (2005) [citation]: "The neuromatrix theory of pain proposes that pain is a multidimensional experience produced by characteristic "neurosignature" patterns of nerve impulses generated by a widely distributed neural network -the "body-self neuromatrix" -in the brain. These neurosignature patterns may be triggered by sensory inputs, but they may also be generated independently of them. Acute pains evoked by brief noxious inputs have been meticulously investigated by neuroscientists, and their sensory transmission mechanisms are generally well understood. In contrast, chronic pain syndromes, which are often characterized by severe pain associated with little or no discernable injury or pathology, remain a mystery. Furthermore, chronic psychological or physical stress is often associated with chronic pain, but the relationship is poorly understood. The neuromatrix theory of pain provides a new conceptual framework to examine these problems. It proposes that the output patterns of the body-self neuromatrix activate perceptual, homeostatic, and behavioral programs after injury, pathology, or chronic stress. Pain, then, is produced by the output of a widely distributed neural network in the brain rather than directly by sensory input evoked by injury, inflammation, or other pathology. The neuromatrix, which is genetically determined and modified by sensory experience, is the primary mechanism that generates the neural pattern that produces pain. Its output pattern is determined by multiple influences, of which the somatic sensory input is only a part, that converge on the neuromatrix" [4,5].

What beyound neuromatrix?
As it observed, most of the pain theories are not "global" but "localized" to body structures or functions: receptors (intensity and specificity), coding of information (neural patterns), dorsal medulla (portion control theory), central nervous system (neuromatrix theory). Other important elements are the figures of a puzzle -beliefs, memory, previous experiences, stress, central and peripheral sensitization, downward modulation, cortical plasticity and retography, neuroimmuno-humoral mechanisms etc. (Fig. 3).
The human body is whole. Any structure and function at any scale can be studied and presented individually, separately. In reality, however, "everything is connected to everything", functioning as a whole. In this way, each pain theory has its place, reflecting an element in the puzzle. Could a new theory of pain go beyond the neuromatrix scale, so that the puzzle is the final picture?
What would be after neuromatrix? Which elements could complement it?
Here we can mention nonperceptual influences on neuromatrix, its interaction with other body analyzers (seeing, hearing, smell, taste, touch). Recent studies have found the connections between the olfactory analyzer and the visual eye with neuromatric pain. Applications, which will clarify these issues, are of the future [8,9,10].

Brain matrix and the missing element of pain: gut microbiota
From a certain point of view, humans can be considered superorganisms, which are composed of the human and the microbial component. With the help of contemporary biotechnology and information technologies, it has been found that microbial communities within the human body can alter their lifestyle, behavior, influence the perception of pain or induce/favor the occurrence of many diseases (Fig. 4).
The human intestine hosts, under anaerobic conditions, over 100 trillion microorganisms, which are representative of over 1.000 distinct species. Recently, there was a bidirectional link between the intestine and the brain, where the microbial composition can influence behavior and cognition, and the nervous system in turn -the microbial composition of the intestine. Bacterial metabolites (up to 99 % undetected), vagus nerve, immune system, hypothalamic-pituitary-adrenal axis , short chain fatty acids, such as butyrate[short chain fatty acids, SCFAs]) are able to modulate peripheral and central pathological processes. The role of these substances has already been demonstrated in the generation and maintenance of inflammation, neuroinflamation, acute and chronic pain, obesity, central nervous system disorders [6].
And this new direction of study will, as far as we can see, significantly complement our knowledge of ourselves, including those related to nociception and pain.

Instead of conclusions
Even the most contemporary theories of pain were based on the knowledge gained from older theories. In turn, they will be the platform for generating new knowledges to formulate the next generation of pain theories.  (1) lymphocytes may sense the gut lumen and internally release cytokines which can have endocrine or paracrine actions, (2) Sensory neuronal terminals, such as on the vagus nerve may be activated by gut peptides released by enteroendocrine cells, (3) Neurotransmitters or its precursors produced as microbiota metabolites may reach the gut epithelium having endocrine or paracrine effects. (4) Centrally, after brainstem relays (e.g., nucleus tractus solitarii) a discrete neural network has been described consistently involving the amygdala (Am) and the insular cortex (IC) as main integrators of visceral inputs. Consistently hypothalamic (Hy) activation initiates the efferent arm (red arrows): (5) corticosteroids, release as results of the hypothalamic-pituitary-adrenal (HPA) axis activation, modulates gut microbiota composition. (6) Neuronal efferent activation may include the so called "anti-inflamatory cholinergic reflex" and/or sympathetic activation, both liberating classica neurotransmitters that may affect directly the gut microbiota composition.