Part II - Nociceptive pain - A historical overview

A historical overview of nociceptive pain confirms its scientific status.

Charles-Edouard Brown-Séquard (1817-1894), a prominent British neurologist at the time, was the first to describe the mostly irreversible sensory and motor consequences of a lesion of various nerve fibres in the spinal cord as a result of an injury. On the one hand, he registered the loss of position sense and pressure sensitivity as well as an increase in pain and temperature sensitivity; on the other hand, he noted motor failures of the vascular and skeletal muscles. 
In 1887, the Spanish histologist Santiago Ramón y Cajal (1852-1934) clearly recognised a network of separate cells in the brain cells prepared by the Italian physician Camillo Golgi, whereas until then it had been assumed that the nervous system was a single net-like structure. These individual cells (neurons) can work independently and form multiple synaptic connections. Altering these synaptic connections allows for growth and adaptation.
In 1920, neurologist Sir Henry Head (1861-1941) presented his "specific fibre theory": specific nerve fibres with specific mechanosensory organs for specific sensory modalities such as superficial, fine and deeper, coarser sensibility and proprioception (the sixth sense). 
Inspired by Cajal's work, the British neuropsychologist Charles Scott Sherrington (1857-1952) continued to research the functioning of neurons, particularly the myogenic reflex mechanism and the mechanism of action potential initiation and transmission. He introduced the terms synapses, proprioception, reciprocal innervation and nociceptor. Based on animal samples, Sherrington was able to describe the consequences of peripheral nerve damage such as sensory and motor deficits as well as coordination disorders. For this groundbreaking work, he was awarded the Nobel Prize for Medicine in 1932. 
Although the Italian physician and physicist Luigi Aloisio Galvani discovered more or less accidentally in 1791 the phenomenon of muscle movements as a result of an electrical force, such as the vibration of the thighs of dissected frogs, it was the British physiologists and biophysicists Alan Lloyd Hodgkin (1917-2012) and Andrew Fielding Huxley (1914-1998), in cooperation with the Australian physiologist, neuroscientist and philosopher John Carew Eccles (1903-1997), who almost 200 years later, inspired by the work of Sherrington, thoroughly researched and described the action potential and the inhibiting/facilitating electrical transmission of impulses via nerves. For this they received the Nobel Prize in Physiology or Medicine in 1963.

Nociceptors as the starting point for nociception are sensory receptors for noxious (harmful or threatening to the organism) stimuli that are found almost everywhere in the body. Nociceptive afferents are specific for the perception of noxious thermal, mechanical and chemical stimuli. Irritation of a nociceptor leads to the familiar "Ouch!" reaction.
The American neuroscientist Edward Roy Perl (1926 - 2014) focused his research on the neural mechanisms and circuits involved in somatic sensations, especially nociception. In the late 1960s, together with his then PhD student Paul Richard Burgess, he demonstrated in pioneering experiments the existence of a class of unique nociceptors: thin myelinated fast-responding A afferents with a higher response frequency, and the largely non-specific slower-responding polymodal C afferents with more connections to the spinal cord. 
He distinguished three groups of nociceptors: Mechanonociceptors associated with A afferents (Aδ-fibres - responsible for well-localised sharp stabbing pain and protective reflexes and the Aγ-fibres mediating pinpricks, itching and other mechanical pain sensations) and polymodal nociceptors, which additionally respond to heat, cold and chemical pain stimuli and can be divided into Aδ-polymodal nociceptors and C-polymodal nociceptors depending on the fibre properties (transmit dull, flat burning longer-lasting, delayed pain stimuli). The third group comprises the silent nociceptors that cannot be excited in healthy tissue. These can only be activated when their stimulus threshold is lowered to a particularly sensitive level by inflammation (endings of C-fibres). Bradykinin, for example, excites predominantly high-threshold afferents, prostaglandins predominantly low-threshold afferents. 
In the case of nociceptors in deep tissues such as muscles, joint capsules, tendons and ligaments, this different sensitivity is a decisive factor. This difference in sensitivity is a decisive criterion for the basic classification of afferents into low-threshold mechanosensors and high-threshold nociceptors. Thus, ischaemia is probably one of the most important stimuli for a certain group of muscle nociceptors, which are particularly excited by contraction under ischaemic conditions, i.e. ischaemia sensitises to mechanical stimuli (ischaemic contractions are also strongly painful in humans). 
For most afferents of the knee joint (capsule, tendons and ligaments), movement intensity is an important stimulus for activation. Low-threshold afferents already respond to normal (non-noxious) passive movements in the joint, while mechanical high-threshold afferents only respond to (noxious) overstretching or twisting of the joint ("classic nociceptors"). In between, there is a group of afferents that are activated only slightly during non-noxious movement, but strongly during noxious movement. Other afferents do not respond to movement at all, although a receptive field is found in the knee joint. 
The last few decades of work in the Perl lab have been devoted mainly to integrating nociceptive and non-nociceptive information from the periphery in areas of the superficial dorsal horn and understanding how spinal neurons located in these regions interact with each other to process signals from the periphery.
Sensory researchers David Julius and Ardem Patapoutian, Nobel Laureates in Medicine 2021, have further deciphered how the sensors for pain, heat, cold, touch and proprioception function at the molecular level and have discovered how stimulation of these sensors is converted into an electrical signal that is transmitted via nerve fibres to the brain, where perception then takes place.

Once an adequate stimulus in a sensory organ is converted into an action potential, the neurons are also excited. For this purpose, each nerve cell has several, sometimes very many smaller, branched dendrites for feeding the signals to the cell body and an axon up to 1 m long for guiding the signal away from the cell body. The axon splits into many branches at its end, each ending at a contact point, synapse, with numerous other dendrites. All these dendrites, which originate from all possible regions of the body (internal organs, psychosocial influences), exert inhibitory or promoting influences on the original (pain) stimulus via the animate and autonomic nervous system.
In addition, the action potentials generated by activation of peripheral nociceptors in the sensory dorsal horn in the spinal cord are transmitted to secondary afferents, which are then projected into the brain for processing. Intense tissue injury can cause sensitisation processes at these switch points in the spinal cord than in the brain.
In addition, many psychosocial factors can also exert an influence on the perception of nociceptive pain. This should be taken into account at all times in the assessment of chronic pain. A complete treatment of chronic back pain consists of a biomedical part and a psychosocial part.  
For example, specific training can influence the tissues that contain many nociceptors, such as subchondral bone tissue and fascial tissue, so that the discharge frequency of these nociceptors decreases and thus less pain is felt. Depending on the condition of these tissues (degree of osteoarthritis) and the specificity of the training, this influence can be large or small, temporary or permanent. For this, cooperation of the patient, education and reduction of fear of movement, among other things, is crucial.

Richly supplied with noceptors are the connective tissue-like skins and sheaths such as meninges (meninges), parietal peritoneum and pleura (peritoneum and pleura), periosteum and epithelia of Haversian and Volkmann canals, myogenic fascia, fibrous outer membrane of the joint capsule, vertebral longitudinal ligaments closely associated with the intervertebral discs, tendons, cruciate ligaments of the knee joint (the anterior cruciate ligament consists for 3-4 % of nociceptors and mechanoreceptors) and especially to mention the subchondral bone tissue. This tissue contributes significantly to shock absorption and force transmission to the deeper bone tissue and to the load-bearing capacity of the joint because of its relative deformability, thickness and the capillary system present, and plays a significant role in pain sensitivity because of the extremely abundant nociceptors and mechanosensors, the mechanical irritation of which is often the cause of joint pain.
The density of nociceptors is also particularly high in the skin, greater than all other skin receptors. 

Excluded from nociceptors are visceral organs such as the brain and peripheral nerves (!), cartilage (of joints and intervertebral disc), thyroid, pancreas, kidneys, adrenal glands, inner synovial membrane of joints, bone tissue, uterine body, visceral peritoneum (peritoneum, visceral pleura (pleura of the lungs), visceral pericardium, retina, lens of the eye and enamel.

Conclusion
Whereas in nociceptive pain the nerve pathways have been scientifically established to act as "transmitters" of (pain) stimuli, in the hypothetical concept of neuropathic pain there is still a view that nerve fibres as a result of damage can also act as "sensory organs".

Pain caused by nociceptive stimulation is virtually identical to pain caused by presumed ectopic stimulation of nerve fibres (neuropathic pain).

Nociceptive pain, unlike neuropathic pain, has a scientific basis and a growing body of clinical evidence shows that alleged neuropathic pain is ultimately nociceptive in nature.

Nociplastic pain arise exclusively from altered nociception and play a crucial role in the biopsychosocial model.