In the entire history of medicine, only about 100 cases have been established when people were born who were completely insensitive to pain.

Pain is a social problem. According to the WHO, every day up to 3.5 million people suffer from pain, while 50% — moderate pain, about 30% — intolerable, 50-80% of cancer patients do not receive satisfactory pain relief. The problem of pain worried doctors in ancient times. By now, there are several points of view on the problem of pain.

Until now, there is no unified theory of pain explaining its various manifestations [4]. The most important theories of pain for understanding the mechanisms of pain formation are:

The theory of «gate control» by R. Melzak and P.D. Walla

As applied to the theory of «gate control», a mechanism for controlling the passage of nociceptive impulses from the periphery functions in the afferent input system in the spinal cord. This control is carried out inhibitory neurons of the gelatinous substance, which are activated by impulses from the periphery along thick fibers, as well as by descending influences from the supraspinal regions, also the cerebral cortex. This type of control is, figuratively speaking, a «gate» that regulates the flow of nociceptive impulses. Based on the beliefs of this theory, pathological pain occurs when there is a deficiency of the inhibitory mechanisms of T-neurons, which, being disinhibited and activated by various stimuli from the periphery and from other sources, send intense ascending impulses.

At this time, the hypothesis of the «gate control» system has been replenished with almost all the details, and the essence of the idea contained in this essence, which is important for the clinician, remains and is widely accepted. Still, according to the creators themselves, the theory of «gate control» is not able to explain the pathogenesis of pain of central origin. Portal pain control theory describes why non-painful stimuli can suppress the responses of neurons in the dorsal horn of the spinal cord, which transmit information to the brain about painful stimuli — for example, when an injured part of a limb is compressed when afferent Aδ fibers are excited

In the context of this theory, one can explain the high efficacy of preventively used analgesics in relation to the same analgesics and in the same doses, but used in a patient in a more severe phase of pain syndrome.

The neurons of the gelatinous substance are influenced by descending pathways from the thalamus, non-nociceptive influences from afferent Aβ-fibers, nociceptive influences from afferent Aδ-fibers

This leads to difficulty in conducting nociceptive impulses through the gelatinous substance and a decrease in the power of the impulse stream, which, having passed through the thalamus and reaching the cortex, forms a sensation of pain.

If the activity of C-fibers increases, then the conduction of excitation through the gelatinous substance is facilitated.

Pain control gateway diagram

(Gritsay A.N., 2013)

JS — gelatinous substance of the posterior horns of the spinal cord

T-transmission neurons

L — large diameter fibers

S — small diameter fibers

1. Transmission of nerve impulses to the central nervous system is modulated by special «gate» mechanisms, which are located in the posterior horns of the spinal cord.
2. Spinal gate mechanisms represent the relationship between the activity of large-diameter afferent fibers (L) and small-diameter fibers (S): the activity of L-fibers inhibits the transmission of impulses («closes the gate»), while the activity of S-fibers facilitates their transmission («Opens the gate»).
3. Spinal «gate» mechanisms, for their part, are also regulated by descending impulses from the brain, which are activated by a system of large-diameter fast-conducting fibers (L).
4. When the critical level is reached, the flow of impulses from the neurons of the spinal cord (relay, transmission neurons, transmitting T cells) activates the system of action, that is, those neuronal zones of the central nervous system that form complex behavioral responses to pain.

The theory of generator and system mechanisms G.N. Kryzhanovsky

More optimal for the purpose of understanding the elements of the mechanisms of central pain is the concept of generator and systemic mechanisms of pain, formed by G.N. Kryzhanovsky, who believes that the powerful nociceptive activation coming from the periphery generates a stream of actions in the cells of the dorsal horns of the spinal cord, which are triggered by excitatory amino acids (glutamine) and peptides (in particular, substance P).

In addition, pain syndromes can arise due to the activity in the pain sensitivity system of new pathological integrations — an aggregate of hyperactive neurons, which is a generator of pathologically enhanced excitation and a pathological algic system, which is a new structural and functional organization consisting of primary and secondary altered nociceptive neurons, and which is the pathogenetic base of pain syndrome [1].

Any major pain syndrome has its own algic organization, into the structure of which, as a rule, destruction of 3 levels of the central nervous system is introduced: the lower trunk, the diencephalon (thalamus, combined lesion of the thalamus, basal ganglia of the inner capsule), cortex, adjacent white matter of the brain.

The type of pain syndrome, its clinical characteristics are formed by the structural-multifunctional system of the pathological algic concept, but the extent of the pain syndrome, as well as the type of pain attacks, depend on the distinctive features of its activation and still work. Formed under the influence of painful impulses, this concept independently, in the absence of additional special stimulation, can also improve its own activity, acquiring stability to the effects of the antinociceptive system and to the perception of a single integrative control of the central nervous system.

The formation and stabilization of the pathological algic system, as well as the development of generators, explain this fact, that surgical elimination of the primary source of pain is far from always effective, but in some cases only leads to a temporary reduction in the severity of pain. In an extreme case, after a certain period, the activity of the pathological algic system is resumed and a resumption of the pain syndrome appears [4]. Of the probable mechanisms of the onset of basic pain, the following are more significant:

• loss of the main inhibitory effect on myelinated primary afferents;
• reorganization of connections in the zone of afferent structures;
• spontaneous activity in the spinal neurons of pain sensitivity;
• deficiency (admissible genetic) of endogenous antinociceptive structures (reduction in the level of enkephalin and serotonin metabolites in cerebrospinal fluid).

Theories that consider the neuronal and neurochemical aspects of pain formation.

The existing pathophysiological and biochemical theories complement each other and form a holistic understanding of the main pathogenetic mechanisms of pain. Thus, for example, in addition to opioids, there are also other neurotransmitter mechanisms of pain suppression [2]. The stronger of them is considered to be serotonergic, interconnected with additional activation of other brain structures (large nucleus of the suture, etc.). The activation of these structures generates an analytical effect, but serotonin antagonists eliminate it.

The basis of the antinociceptive effect is the direct, descending, inhibitory effect of these structures on the spinal cord. There is evidence that the analgesic effect of acupuncture is realized through opiate and, in part, serotonergic mechanisms.

In addition, there is a noradrenergic mechanism of antinociception, mediated by emotiogenic areas of the hypothalamus and the reticular formation of the midbrain. Positive and negative feelings are willing to increase or control pain. The extreme limits of emotional stress (stress) usually lead to suppression of the feeling of pain. Negative feelings (anxiety, rage) block pain, which allows you to quickly fight to save life, despite the possible injury.

This type of normal stress analgesia in some cases is reflected in the background of a pathological affective state. The analgesic effect of stimulation of emotiogenic zones in animals is not blocked by opioid and serotonin antagonists, but is inhibited by adrenolytic agents, facilitated by adrenomimetics. Substances of this class, in particular clonidine and its analogs, are used to treat a specific type of pain.

Several non-opioid peptides (neurotensin, angiotensin II, calcitonin, bombesin, cholecystotonin), in addition to their own peculiar hormonal effects, are ready to exhibit an analgesic effect, while revealing a specific selectivity in relation to somatic, visceral pain. Certain structures of the brain involved in the conduct of pain excitement and creating specific elements of the pain reaction are highly sensitive to specific drugs and substances. The use of such agents can selectively regulate these or other manifestations of pain.

At the same time, the antinociceptive properties of cannabinoid receptor agonists were demonstrated in behavioral and electrophysiological experiments using models of severe pain and inflammation, interacting with peripheral CB1 receptors.

Cannabinoid CB1 receptors are found in numerous structures — peripheral and central, involved in the processes of transmission and perception of nociceptive signals. It was noted that medium and large neurons in the dorsal root ganglia of rats synthesize cannabinoid receptors, which are subsequently transported along axons to the peripheral ends of the primary afferent fibers. Found co-expression of CB1 receptors and vanilloid VR1 receptors in rat DRG neurons. This suggests a particular interest due to the fact that the endocannabinoid anandamide is considered a two-species agonist. Cannabinoid receptors are also found in the spinal cord, mostly on interneurons.

CB2 receptors are found to a greater extent in immunocompetent cells, where they mediate the immunosuppressive effect.

Although mRNA of CB2 receptors was not found in the neural tissue of the brain of humans and rats, it was confirmed that it was present in the microglia of the latter. There are reports of the presence of mRNA for CB2 receptors, along with mRNA for CB1 receptors, in the cerebellum of mice.

The presence of peripheral application of anandamide inhibits hyperalgesia stimulated by injection of carrageenan, due to the stimulation of CB1 receptors [1]. In addition, peripheral administration of both anandamide and the selective CB2 agonist palmitylethanolamide suppresses formalin-initiated behavioral nociceptive responses. These inhibitory effects are blocked by antagonists of the CB1 and CB2 receptors, respectively. The extremely significant role of presynaptic cannabinoid receptors of DRG neurons in the mechanisms of the analgesic effect of cannabinoids was confirmed, which is manifested by a decrease in the release of mediators at the level of the spinal cord.

The evidence that cannabinoid receptor agonists have the potential to suppress pain by interacting with peripheral CB1 receptors is both theoretical and practical. First of all, the data suggest that modulation of the nociceptive signal is likely at the initial stage of pain perception by a peripheral control (“gate”) mechanism, where endogenous cannabinoid lipids can function in cooperation with opioid peptides [2]. In this case, there is a fundamental possibility of influencing pain sensitivity, avoiding the psychotropic effect of cannabinoids, which is predetermined by interaction with CB1 receptors in the brain.

The results of behavioral and electrophysiological studies indicate that with spinal methods of administration (under the meninges of the brain, into the gray matter of the spinal cord), natural, artificial and endogenous cannabinoids activate antinociceptive and antihyperalgesic effects in models of acute pain and also inflammation.

The significant importance of the supraspinal element in modulating nociception by cannabinoids is emphasized by the fact that the presence of peripheral nociceptive stimulation is fixed by the release of anandamide in PAG, one of the more significant structures of the natural antinociceptive system.

In studies devoted to the disclosure of the analgesic properties of cannabinoids, agonists with a comparable affinity for CB1- and CB2 -receptors were used more. But the antinociceptive effect of cannabinoids was largely blocked by the selective CB1 receptor antagonist SR 141716A. In animals that were injected with this substance, the behavioral responses to formalin (intradermally) as well as the nociceptive responses of the dorsal horn neurons in the spinal cord increased, which indicates the participation of CB1 receptors in the transmission of nociceptive signals under normal conditions.

In the final period, active and selective agonists of CB1 receptors (arachidonyl-2-chloroethylamide, arachidonylcyclopropylamide) were obtained, but the analgesic properties of these compounds have not yet been studied [4].

Of particular interest to the clinic are the analgesic properties of cannabinoids in circumstances of hyperalgesia (increased response to painful stimulation) and / or allodynia (painful response to non-nociceptive stimulation).

Thus, an agonist of cannabinoid receptors WIN 55212-2, when administered spinal to rats, inhibits “mechanical” allodynia, stimulated by the injection of Freund’s complete adjuvant, by interacting with CB1 receptors. At the same time, the anti-allodynic effect of the element is traced in doses that are minimal than analgesic, which indicates an increase in sensitivity to cannabinoids during the formation of allodynia. In behavioral experiments with systemic and spinal administration, cannabinoids reduce mechanical and thermal allodynia in rat models of neuropathic pain.

The supraspinal location of cannabinoid exposure in neuropathic pain has not been systematically studied, but it has been shown that with an afferent nerve defect, an increase in the number of CB1 receptors (up-regulation) in the contralateral thalamus is recorded. It is believed that this manifestation may explain the effectiveness of cannabinoids in chronic pain models [5].

In the past years, a line of mice with a defect in the gene that regulates CB1 receptors was obtained. In animals “knocked out” by the CB1 receptor, the duration of existence is reduced, a decrease in motor activity, catalepsy, and hypoalgesia are noted.

Experimental and isolated medical studies have determined the effectiveness of antagonists of cannabinoid CB1 receptors as anorexigenic agents in the treatment of schizophrenia, disorders of cognitive functions and memory in certain neurodegenerative diseases (Alzheimer’s disease, etc.).

Agonists of CB1 receptors, in addition to stimulating appetite and antiemetic activity, express neuroprotective properties (due to suppression of the release of glutamate in the central nervous system). Their effectiveness was determined for disorders of motor function (muscle rigidity, tremors) in multiple sclerosis, as well as traumatic defects of the spinal cord, tics and psychological disorders in Tourette’s syndrome, dyskinesias formed in the treatment of Parkinson’s disease with levodopa. CB1 receptor agonists exhibit pronounced analgesic activity. They are used, in turn, to cure glaucoma; they have been found to have antitumor properties [5].

Cannabinoid CB2 receptor agonists that have anti-inflammatory and immunosuppressive effects are of interest. Compounds that do not cross the blood-brain barrier, multifunctional organization, and therapeutic potential could enhance the analgesic effect in inflammatory processes in the absence of side effects due to the effect on the central nervous system [3].

Certain substances containing cannabinoid receptor ligands are used in medical practice. Thus, in the United States, Δ9-tetrahydrocannabinol (THC) is prescribed orally (dronabinol, syn. Marinol) in order to prevent and relieve nausea during chemotherapy of tumors, but in addition to stimulate appetite in case of a significant decrease in body weight in patients with acquired immunodeficiency syndrome. Nabilone, a synthetic analogue of THC (syn. Cesamet), is used in the UK as an antiemetic agent [1]

The theory of intensity was proposed by the English physician E. Darwin (1794), according to which pain is not a special feeling and does not have its own special receptors, but appears as a result of the action of superstrong stimuli on the receptors of five known sensory organs. The formation of pain involves the convergence and summation of impulses in the spinal cord and brain.

The theory of specificity was set forth by the German physicist M. Frey (1894). According to this theory, pain is a special feeling (sixth sense), which has its own receptor apparatus, afferent pathways and structures of the brain that processes pain information. M. Frey’s theory later received a more complete experimental and clinical confirmation

Pain is a reflex process that includes all the main links of the reflex arc: the receptor apparatus, pain conductors, formations of the spinal cord and brain, as well as mediators that transmit pain impulses.

Correct and effectively selected drug pain relief can facilitate patient recovery, improve the state of life, accelerate the recovery of body functions and reduce the risk of pain becoming chronic.