Pain is caused by injurious stimuli that can damage the body’s tissues and is a form of protective adaptation to the surrounding environment. The mechanisms of its formation include both peripheral and central nervous mechanisms.
I. Peripheral nerve mechanism of p pain
The peripheral nerve mechanism of pain refers to the process by which various receptors distributed in different parts of the body convert painful stimuli into corresponding information and are transmitted to the central nervous system (CNS) by the corresponding sensory nerve fibers.
(i) Injury receptors
Injury receptors are peripheral transducers of nociceptive signals, mainly located in the skin, mucosa, gastrointestinal mucosa and subplasma layer, intermuscular connective tissue, tendon surface and interior, deep fascia, periosteum and vascular epicardium. Primary afferent injury receptors are generally considered to be terminal branches of Aδ and C fibers, which are morphologically “free” or undifferentiated nerve endings with cell bodies located in the dorsal root ganglion. According to the location of injury receptors and their sensitivity to different stimulation conditions, they are divided into three different types: surface injury receptors, muscle p-joint injury receptors and visceral injury receptors.
(ii) Injury receptor afferents
The nerve fibers associated with injury sensory transmission include Aδ fibers and C fibers. However, these fibers are not simple transmitters of sensory information. Recent studies have shown that severed or injured peripheral nerves act as a painful lesion in their own right and cause many physiological, morphological and biochemical changes, such as abnormal activity in the peripheral primary afferent terminals or dorsal root ganglia.
(iii) Peripheral sympathetic fiber activity and pain
The sympathetic nervous system has an important role in the development and persistence of chronic pain. Nerve injury or even minor trauma can lead to sympathetic dysfunction, and sympathetic dysfunction is closely associated with the development of “complex localized pain syndrome”, which is often accompanied by sympathetic dysfunction, manifested by burning pain, nociceptive hyperalgesia and touch-evoked pain (allodynia ). Studies have confirmed that after peripheral nerve injury, its formation of new sprouts (sprout) is very sensitive to α-adrenergic agonists, and the presence of α-adrenergic receptors on the dorsal root ganglion and the formation of innervation between the dorsal root ganglion and the terminals of sympathetic efferent fibers have also been found, implying that the activity of sympathetic efferent fibers can abnormalize the activity and response of peripheral afferent fibers.
(iv) Peripheral sensitization
During tissue injury and inflammatory responses, the release of inflammatory mediators from injured cells such as mast cells, macrophages and lymphocytes, and injurious stimuli also lead to neurogenic inflammatory responses, resulting in vasodilation, plasma protein leakage as well as acting on inflammatory cells that release chemical mediators. These interactions lead to the release of inflammatory mediators such as K+, H+, serotonin, bradykinin, substance P (SP), histamine, nerve growth factor, cyclooxygenase and lipoxygenase pathway metabolites of arachidonic acid metabolism (e.g., prostaglandins, leukotrienes, etc.), and calcitonin gene-related peptide (CGRP), which are chemicals or inflammatory mediators that make low-intensity that do not cause pain in normal stimuli that do not normally cause pain can also cause pain. This series of changes that occur after tissue injury is called peripheral sensitization. If peripheral injury receptors are sensitized, this can be manifested as.
(1) pain at rest or spontaneous pain (spontanous pain);
(2) primary hyperalgesia (primary hyperalgesia); (3) touch-evoked pain.
II. Central neural mechanisms of p-pain
(i) Termination of primary afferent fibers in the dorsal horn of the spinal cord
The dorsal horn of the spinal cord is the first relay station for the transmission of injurious information to the center. Primary afferent injurious receptors terminate mainly in laminae I, II and V of the dorsal horn of the spinal cord, with C fibers terminating in laminae I, II and III and Aδ fibers terminating in laminae V in addition to laminae I, II and III. The posterior horn glia (laminae II and III) is an important site for the modulation of injurious information.
(ii) The upstream pathway that transmits nociceptive information
The afferent impulses from the injurious receptors, after the initial integration of neurons in the dorsal horn of the spinal cord, enter the higher parts of the center by an upstream pathway. The superior pathways transmitting nociceptive information include the spinal thalamic tract (STT), spinal reticular tract (SRT), spinal midbrain tract (SMT), spinal cervical nucleus tract (SCT), dorsal column postsynaptic fiber tract (PSDC), spinal paraspinal amygdaloid tract (SPAT), spinal paraspinal hypothalamic tract (SPHT), and spinal hypothalamic tract (SHT). Among these nociceptive transmission bundles, SRTpSCT and PSDC conduct fast pain, while STTpSMTpSPATpSPHT and SHT conduct both fast and slow pain.
(iii) Nociceptive centers
1.Subcortical centers
The subcortical centers involved in the integration, modulation and perception of pain mainly refer to the thalamus, hypothalamus and some nuclei and neurons in the brain. The nuclei that are closely related to pain transmission in the thalamus include the medial nucleus and the posterior lateral nucleus in the lateral nucleus group, the posterior medial nucleus and the parabasal nucleus in the medullary plate nucleus group; the preoptic and anterior hypothalamic areas of the hypothalamus, the ventral medial nucleus of the hypothalamus, and the periventricular nucleus contain pain-sensitive neurons that are excitatory or inhibitory in response to injurious stimuli. These neurons play a role in the regulation of pain to a greater or lesser extent.
2. Cerebral cortex
The cerebral cortex is the higher center for the integration of sensory discrimination and response impulses to pain. The pain process involves a wide range of regions, while pain impulses necessarily enter the field of consciousness. It is generally believed that the cortical areas involved in the whole process of pain are the first p two p three sensory areas and the limbic system. The first sensory area is the sensory discrimination area of pain; the second sensory area mainly feels visceral pain; the third sensory area is involved in the discrimination of deep sensation and pain response activities; the limbic system is mainly involved in the modulation of visceral pain and psychogenic pain.
(iv) Central sensitization
After tissue injury, there is an enhanced response to normal innocuous stimuli (touch-evoked pain) and an overreaction not only to mechanical and thermal stimuli from the injured area (primary nociceptive sensitization), but also to mechanical stimuli from the undamaged area surrounding the injured area (secondary nociceptive sensitization). All of these changes are the result of increased excitability of spinal cord dorsal horn neurons after injury, i.e., central sensitization.
Repeated and persistent stimulation of C-fibers of primary afferent neurons results in substantial alterations in CNS function and activity. After tissue injury, injurious stimuli are afferent via C fibers and release transmitters or modulators such as glutamate, SP, CGRP, and nerve growth factor, which act on the corresponding receptors, such as N-methyl-D-aspartate (***A) and non-***A receptors, and neurokinin (NK)1 receptors, resulting in an activity-dependent increase in the excitability of spinal cord dorsal horn neurons. Injurious stimuli increase the release of peptide transmitters from primary afferent fibers, increase Ca2+ inward flow, activate the second messenger system, alter the activity of protein kinases (PKC, PKA, PKG, aCaPK II) and phosphorylate proteins. During prolonged inflammation, activation of protein kinases produces transcriptional variants that result in increased responsiveness of spinal cord dorsal horn cells to extant afferent impulses and to original subthreshold afferent impulses, producing
(i) enhanced response to normal stimuli ;
(ii) an enlarged receptive area and
(iii) a decrease in the activation threshold of the new afferent impulse.
(E) Central adjustment mechanism of pain
After the impulses of peripheral injurious stimuli are transmitted, nociception is perceived or suppressed by the adjustment of the central levels. Neurophysiological studies have confirmed that stimulation of a wide range of brain regions can inhibit the injurious pain response, which means that the central nerve has an inhibitory effect on the injurious afferent impulses. This inhibitory effect is on the one hand through segmental mechanisms and on the other hand from the higher centers in a downward direction.
1. Segmental inhibition mechanisms
Segmental inhibition is a response through segmental connections between fibers in different segments of the spinal cord, which are part of the reflex arc in the spinal cord. Segmental inhibition is mainly manifested as a response of broad-powered or specific injurious sensory neurons in the dorsal horn, which can be selectively inhibited by input from the spinal cord level.
2.Brainstem downward inhibition mechanism
The central structures of brainstem descending inhibition consist of three main parts.
(i) periaqueductal gray matter (PAG) of the midbrain.
(ii) The ventral medial cephalic reticular formation (RVM) of the delayed brain.
(iii) The dorsolateral parietal cap of the pontocerebrum (DLPT).
For the brainstem inferior nociceptive modulation system, its normal function is mainly related to noradrenergic neurons, 5-hydroxytryptaminergic neurons and endogenous opioid peptides. In addition, γ-aminobutyric acid and growth inhibitory hormone also play an important role.