Pain: current aspects on peripheral and central sensitization

Abstracts

JUSTIFICATIVA E OBJETIVOS: As pesquisas recentes têm focalizado a plasticidade bioquímica e estrutural do sistema nervoso decorrente da lesão tissular. Os mecanismos envolvidos na transição da dor aguda para crônica são complexos e envolvem a interação de sistemas receptores e o fluxo de íons intracelulares, sistemas de segundo mensageiro e novas conexões sinápticas. O objetivo deste artigo foi discutir os novos mecanismos que envolvem a sensibilização periférica e central. CONTEÚDO: A lesão tissular provoca aumento na resposta dos nociceptores, chamada de sensibilização ou facilitação. Esses fenômenos iniciam-se após a liberação local de mediadores inflamatórios e a ativação de células do sistema imune ou de receptores específicos no sistema nervoso periférico e central. CONCLUSÕES: As lesões do tecido e dos neurônios resultam em sensibilização de nociceptores e facilitação da condução nervosa central e periférica.

DOR

REVIEW ARTICLE

Pain: current aspects on peripheral and central sensitization^*

Dolor: aspectos actuales de la sensibilización periférica y central

Anita Perpétua Carvalho Rocha^I; Durval Campos Kraychete, TSA^II; Lino Lemonica, TSA^III; Lídia Raquel de Carvalho^IV; Guilherme Antônio Moreira de Barros, TSA^V; João Batista dos Santos Garcia, TSA^VI; Rioko Kimiko Sakata, TSA^VII

^IMestre em Anestesiologia pela FMB – UNESP; Coordenadora do Serviço de Dor Aguda do Hospital da Sagrada Família

^IIProfessor Doutor, Disciplina de Anestesiologia da UFBA; Coordenador do Ambulatório de Dor da UFBA

^IIIProfessor Doutor do Departamento de Anestesiologia da FMB – UNESP; Responsável pelo Serviço de Terapia Antálgica e Cuidados Paliativos

^IVProfessor Doutor do Departamento de Bioestatística do Instituto de Biociências, UNESP

^VProfessor Doutor do Departamento de Anestesiologia da FMB – UNESP

^VIProfessor Doutor da Disciplina de Anestesiologia, Universidade Federal do Maranhão; Presidente do Comitê de Dor da Sociedade Brasileira de Anestesiologia

^VIIProfessor Doutor da Disciplina de Anestesiologia da Universidade Federal de São Paulo. Coordenador do Setor DOR da UNIFESP

^{Correspondence to}

SUMMARY

BACKGROUND AND OBJECTIVES: Current research has focused on the biochemical and structural plasticity of the nervous system secondary to tissue injury. The mechanisms involved in the transition from acute to chronic pain are complex and involve the interaction of receptor systems and the flow of intracellular ions, second messenger systems, and new synaptic connections. The aim of this article was to discuss the new mechanisms concerning peripheral and central sensitization.

CONTENTS: Tissue injury increases the response of nociceptors, known as sensitization or facilitation. These phenomena begin after the local release of inflammatory mediators and the activation of the cells of the immune system or specific receptors in the peripheral and central nervous system.

CONCLUSIONS: Tissue and neuronal lesions result in sensitization of the nociceptors and facilitation of the central and peripheral nervous conduction.

Key Words: PAIN: mechanisms, peripheral sensitization, central sensitization.

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Las recientes investigaciones se han centrado en la plasticidad bioquímica y estructural del sistema nervioso proveniente de la lesión tisular. Los mecanismos involucrados en transición del dolor agudo para crónico son complejos e involucran la interacción de sistemas receptores y el flujo de iones intracelulares, sistemas de segundo mensajero y nuevas conexiones sinápticas. El objetivo de este artículo fue discutir los nuevos mecanismos que envuelven la sensibilización periférica y central.

CONCLUSION: La lesión tisular provoca un aumento en la respuesta de los nociceptores, llamada sensibilización o facilitación. Esos fenómenos empiezan después de la liberación local de mediadores inflamatorios y de la activación de células del sistema inmune o de receptores específicos en el sistema nervioso periférico y central.

CONCLUSIONES: Las lesiones del tejido y de las neuronas resultan en una sensibilización de nociceptores y en la facilitación de la conducción nerviosa central y periférica.

INTRODUCTION

Although the International Association for the Study of Pain (IASP) defined pain as a subjective sensation related to tissue injury, there is evidence that this association might not occur. Headache and chronic pelvic pain, for example, seem to exist without tissue damage that can be detected by the diagnostic methods currently available, favoring the hypothesis that there can be neurofunctional changes restricted to the biomolecular level, with the little known interaction among neuromediators, neurotransmitters, and signal transducers in a network of billion of synapses, making it difficult to understand the etiology of pain ¹. On the other hand, trauma and stimulation of the peripheral or central nervous system can also change immune responses. As a consequence, peptides and receptors are activated, followed by the translation of the signal to the intracellular environment. In this context, advances in the knowledge of the neuranatomy of conduction pathways, neuropharmacology, and pathophysiology of pain facilitate the development of research on new treatment modalities. Thus, effective analgesia for painful syndromes is still a great challenge.

In Brazil ² and in other countries ^3,4, 10% to 50% of the people seek clinics to treat their pain ^5-8. In Brazil, pain is present in over 70% of the patients who seek medical attention for several reasons, and is the main reason for the medical visit in one third of the cases. This argument stresses the importance of searching for elements that could lead to a better approach of acute and chronic pain.

The aim of this review was to discuss the pathophysiology of pain, emphasizing the peripheral and central mechanisms of pain transmission.

PERIPHERAL PAIN MECHANISMS

The first step on the sequence of events that originate the painful phenomenon is the transformation of aggressive stimuli in action potentials that are transmitted from the peripheral nerve fibers to the central nervous system ⁹.

Specific pain receptors are located at the nerve endings of Ad and C nerve fibers ^10,11 and, when they are activated, there are changes in their membranes, allowing the deflagration of the action potentials.

Nerve endings of nociceptive Ad and C fibers (nociceptors) are capable to translate an aggressive thermic, chemical, or mechanical stimulus into an electrical stimulus that will be transmitted to the central nervous system and interpreted in the cerebral cortex as pain. The Ad fibers are myelinated while C fibers are non-myelinated; therefore, they are capable of transmitting painful stimuli at different speeds. Due to the presence of the myelin shaft, Ad fibers transmit the painful stimulus fast, while C fibers are responsible for the slow transmission of pain. Both are classified as subtypes Ad1, Ad2, C1, and C2 (Table I). The type of nociceptive fiber seems to be related to distinct peripheral changes on the different painful syndromes and could, in the future, contribute for a more effective pain treatment.

The nociceptors are then sensitized by the action of chemical substances, known as angiogenic, present in the tissue environment ¹²: acetylcholine, bradykinin, histamine, serotonin, leukotriene, substance P, platelet activating factor, acid radicals, potassium ions, prostaglandins, thromboxane, interleukins, tumor necrosis factor (TNFa), nerve growth factor (NGF), and cyclic adenosine monophosphate (cAMP) ^13-15 (Figure 1).

When the stimulus causes tissue injury, the inflammatory process is triggered, which is followed by repair. Damaged cells release their enzymes that, once in the extracellular environment, degrade long chain fatty acids and act on kininogens, originating the kinins. Kinins are small polypeptides of a₂-calicrein present in the plasma or body fluids. Kallikrein is a proteolytic enzyme activated by inflammation and other chemical or physical effects on blood or tissues. Once activated, kallikrein works immediately on the a₂-globulin, liberating the kinin called kallidin that is then converted in bradykinin by tissue enzymes. Once formed, bradykinin causes intense dilation of the arterioles and increases capillary permeability, contributing to the dissemination of inflammattion ¹⁶.

The action of phospholipase A on the cell membrane causes the release of arachidonic acid, which is metabolized by three enzymatic systems: cyclooxigenase that originates prostaglandins, thromboxanes, and prostacyclins; lipoxigenase that induces the production of leukotrienes and lipoxins; and P-450 cytochrome that originates the products of the epoxigenase pathway. These substances, especially prostaglandins E₂ (PGE₂), decrease the excitability threshold of nociceptors ¹⁷. Inflammatory cells, macrophages, and leucocytes release cytokines that contribute to the migration of new cells to the site of injury. There is production and release of interleukins 1 and 6, tumor necrosis factor, selectin, chemotactic factors, nitric oxide, and oxidizing substances. New receptors are then recruited, and participate in the inflammatory process. Substance P and neurokinin A cause vasodilation and increase vascular permeability, which also for maintaining the inflammatory process ¹⁸.

However, bradikinin, prostaglandin E2, nerve growth factor (NGF), and interleukins seem to be fundamental in peripheral nociception. Prostaglandin and bradykinin cause changes in specific receptors (TRPV1) attached to ligand-dependent ion channels through the activation of cAMP and protein kinases A (PKA) and C (PKC), reducing the post-hyperpolarization time of the neural membrane, and decreasing the triggering threshold of the nervous fiber.

Neurotrophins increase the synthesis, anterograde axonal transport, and the amount of SP and CGRP in type 1 C fibers, and reduce the activity of gamma-aminobutyric acid (GABA), both in peripheral and central nerve endings. They also cause changes in the vanilloid receptors (VR1) of Ad fibers attached to ligand-dependent ion channels and trigger protein kinases activated by mitogens (MAPK) that can phosphorilate cAMP and initiate the genetic transcription responsible for phenotypic changes that contribute to the increase in synaptic efficacy.

If the aggression is persistent, it leads to changes in the peripheral nervous system and sensitizes nerve fibers, with consequent hyperalgia and increase in the levels of cAMP and calcium in the nociceptors. This phenomenon is secondary to the action of inflammatory mediators and consequent spontaneous activity of neurons, increase in the response to suprathreshold stimuli, and reduction of the activation threshold of nociceptors ^18-20. An especial type of nociceptor, known as silent nociceptor, is activated after inflammation or after tissue injury. It is estimated that 40% of C fibers and 30% of Ad fibers contribute with silent nociceptors. After the release of chemical products in the lesion, these receptors, previously silent, are activated by thermal and mechanical stimuli, developing spontaneous discharges, being capable of an intense response to nociceptive and non-nociceptive stimuli ^21-22 (Figure 2).

In short, tissue injury results in accumulation of arachidonic acid metabolites. The production of prostaglandins and leukotrienes leads to the degranulation of mast cells and direct activation of nerve fibers, macrophages and lymphocytes. Mediators, such as potassium, serotonin, substance P, histamine, and kinins are released. There are changes in vascular permeability, local blood flow, resulting in the classical signs of inflammation, like erythema, increased temperature, edema, and functional impotence. The process of peripheral sensitization is initiated with the consequent exacerbation of the response to the painful stimulus ^20-22.

Peripheral neuromediators prolong the depolarization of the neural membrane, with the consequent increase of sodium and calcium channels conductivity, and a decrease in the influx of potassium and chloride.

Sodium channels are involved in the genesis of neuronal hyperexcitability and can be classified in two large groups: those sensitive to tetrodotoxin (TTXs), present in Ad fibers, in the entire nervous system, and in the dorsal root ganglion; and those resistant to tetrodotoxin (TTXr), found especially in C fibers of the dorsal root ganglion ²³. Although the peripheral lesion of C fiber decreases SP, neurotrophins (BDNF), receptors (VR1 and P2X₃), and high-voltage type N calcium channels in the dorsal horn of the spinal cord, there is upregulation of type III TTXs channels, and sodium channels (TTXr) are translocated from the cell body to the neuroma, facilitating the increase in nervous excitability ²⁴. This happens if the nerve fiber is intact (inflammation), i.e., there is an increase in excitatory neuromediators in the dorsal horn of the spinal cord and greater expression of sodium channels (TTXr), which facilitates neuronal hyperexcitability and hinders the response to the treatment with local anesthetics ²⁴.

In both situations described, especially in the lesion of C fibers, there can also be an increase in SP and BDNF in Ad fibers (low threshold mechanoreceptors), as well as budding of those at the connections of afferent C fibers (lamina II), increasing the receptive field of the neuron and facilitating the interpretation of harmless stimuli as aggressive ²⁵. This explains, for example, the mechanical allodynia that occurs in post-herpetic neuralgia ²⁶. Other possibility would be the budding of sympathetic noradrenergic axons at the dorsal root ganglion, around large diameter neurons (Ad fibers), suggesting the hypothesis of activation of afferent sensitive fibers after the sympathetic stimulation ²⁷. Besides, there can also be a disproportion between excitatory and pain suppressing pathways, with a decrease in the inhibitory activity of glycine, GABA, and opioids ²⁴.

CENTRAL PAIN MECHANISMS

The transmission of noxious stimuli in the spinal cord is not a passive process. Intraspinal circuits have a capacity to change both the stimulus and painful response. The interaction among the intramedullary circuits determines which messages will reach the cerebral cortex ²¹.

Clinical and experimental studies have demonstrated that noxious stimuli cause changes in the central nervous system, which modify the mechanisms triggered by afferent stimuli. Persistent stimulation of nociceptors causes spontaneous pain, reduces the sensitivity threshold, and causes hyperalgesia. This can be divided in primary and secondary hyperalgesia. Primary hyperalgesia is defined as the increased response to the painful stimulus at the site of injury, while secondary hyperalgesia is the extension of that response to adjacent areas. The presence of all of those elements suggests that peripheral sensitization is not the only phenomena responsible for them, and that the central nervous system must be involved in this process ^21,28,29.

Central sensitization implies changes in peripheral impulses, with positive or negative adaptations. There is a reduction in the threshold or an increase in the response to afferent impulses, persistent discharges after repeated stimuli, and widening of the receptive fields of dorsal horn neurons.

Repeated impulses in C fibers amplify sensorial signals in spinal neurons, sending messages to the brain ¹³. Peripheral lesions induce plasticity in supraspinal structures through mechanisms that encompass specific types of gluatamate receptors. Neurotransmitters, such as substance P, somatostatin, peptide genetically linked to calcitonin, neurokinin A, glutamate, and aspartate are released after tissue injury. These substances are connected to the activation of excitatory post-synaptic potentials, and of N-methyl-D-aspartate (NMDA) and non-NMDA receptors. Frequent stimulation of afferent fibers generates a summation of action potentials and the consequent cumulative pos-synaptic depolarization. After activation of NMDA receptors by glutamate, the ion magnesium is removed from the receptor, leading to the influx of calcium into the cell, amplifying and prolonging the response to the painful stimulus ^30,31.

The increase in calcium concentration leads to activation of nitrous oxide synthase and stimulation of the transcription of protooncogenes. These genes are located in the central nervous system, being involved in the formation of dinorphins and enkephalins. Enkephalins are antinociceptive and connected to the reduction of neuroplasticity and hyperalgia ^32,33. However, dinorphins have a complex mechanism of action, since they have algogenic and antinociceptvie actions.

Recent studies have suggested that the activation of f-fos and c-jun promotes the transcription of the messenger RNA responsible for the synthesis of fundamental proteins involved in changing the phenotypic expression, and the consequent perpetuation of neuronal hypersensitivity ^28,33 (Figure 3).

The sensitization of the dorsal horn of the spinal cord can be of several modalities: wind up, classical synaptic sensitization, long-term potentiation, late phase of the long-term potentiation, and long-term facilitation ³⁴.

The classical synaptic sensitization is caused by a synchronized sequency of repeated peripheral nociceptive stimuli for one asynchronous nociceptive stimulus, increasing the afferent response of Ad and C fibers (homosynaptic potentiation) and the afferent response of non-stimulated Ab fibers (heterosynaptic potentiation). This is a consequence of the release of excitatory amino acids, peptides, and neurotrophins in the dorsal horn of the spinal cord ³⁵.

Excitatory amino acids, represented by glutamate and aspartate, bind to specific ionotropic or metabotropic receptors. In ionotropic, or fast, receptors the neurotransmitter binding site is an integral part of an ion channel, while metabotropic, or slow, receptors are bound to protein G. Among the receptors for excitatory amino acids, we should mention AMPA, cainate, and N-methyl-D-aspartate (NMDA), that are ionotropic, and the Mrglu receptor, whose action is mediated by protein G, making it a metabotropic receptor. Peptides, substance P, and calcitonin gene-related peptide (CGRP) bind to neurokinins type NK-1 and NK-2, while neurotrophins bind to thyrokinases types A and B (trkA and trkB) receptors.

After the release of excitatory amino acids, peptides, and neurotrophins and their binding to specific receptors, there is activation of second messengers, such as cAMP, PKA, PKC, phosphatidylinositol, phospholipase C, and phospholipase A₂. This opens the calcium channels and, consequently, the production of prostaglandins and nitrous oxide, which migrate from the intracellular environment to the synaptic cleft and cause the release of glutamate, aspartate, substance P, and CGRP, contributing to the amplification of the painful process ³⁴.

Wind up is the summation of slow synaptic potentials after repeated low frequency, below 5 Hz, stimulation of the afferent fibers for a prolonged time. This triggers the release of excitatory neurotransmitters, glutamate, and aspartate in the dorsal horn of the spinal cord and produces depolarization secondary to the removal of the voltage-dependent blockade caused by the presence of magnesium in NMDA receptors. There is an increase in calcium conductivity and response to pain to each repeated stimulus of the same intensity ³⁶.

Although long-term potentiation is better known in the hippocampus and cortical areas, it may be the result of a sequence of short, high frequency nociceptive stimuli. This would activate AMPA and NK1 receptors and calcium channels, leading to the prolonged, excitatory post-synaptic response, especially in the neurons in lamina I ³⁷.

The mechanisms that contribute to the increased efficacy of synaptic transmission would be the result of phosphorylation of membrane receptors and changes in the opening time of ion channels, or the formation and transport of excitatory substances from the cell to the synaptic cleft. Besides, proteinokinases activated by mitogens (MAPK) in the dorsal horn of the spinal cord modulate the phosphorylation of NMDA and AMPA receptors, amplifying the nociceptive response ³⁸.

Long-term facilitation involves the activation of transcription factors and changes in transcription. Transcription factors modulate the relationship between the receptor-neuromediator complex and changes in gene expression ³⁹.

The nociceptive stimulus triggers the same receptor cascade and second messengers described previously for the classical synaptic sensitization, but it also triggers the expression of immediate early genes c-fos (B, C, D), c-jun, COX-2 enzymes, and slow response genes that encode pro-dinorphin, NK1 receptor, and trkB in the dorsal horn of the spinal cord. There is upregulation of the pathways for the synthesis of cytokines, chemokines, and adhesion molecules. This causes phenotypic changes in the dorsal root ganglion ⁴⁰.

SEGMENTAR AND SUPRA-SEGMETAR RESPONSES TO PAIN

Nociceptive fibers cross the midline at the level of dorsal horn of the spinal cord and ascend through the spinothalamic, spinoreticular, and spinomesencephalic tracts, post-synaptic posterior column, and spino-ponto-amigdala system. Some of those fibers end at the ventroposteromedial thalamic nucleus (VPM) and ascend posteriorly to the somesthesic (S1 and S2) cerebral cortex, insular cortex, and posterior cingular cortex. Other neurons project their axons to the hypothalamus, reticular formation, periaqueductal gray matter, medial and intrathalamic nucleus, and anterior brain structures responsible for the neuroendocrine and emotional responses to pain ⁴¹.

The activation of peripheral nociceptive fibers leads to retrograde migration of nerve growth factor (NGF) to the spinal cord and induces reflex segmental response with anterograde transport of substance P to the periphery, causing vasodilation, increase in vascular permeability, attraction of cells of the immune system to the site of injury, and degranulation of mast cells and the release of several neuro mediators. Thus, substance P helps the maintenance and expansion of the inflammatory process to the receptive field of nerve fibers adjacent to the site of injury, constituting the secondary hyperalgia ⁴².

On the other hand, adrenergic fibers contribute not only to the process described above but also increase the sensitivity of nociceptive fibers to bradykinin. Vasospasm, muscular spasm, reflexes that trigger the release of acid radicals and, consequently, reduce the discharge threshold for nociceptive fibers, potentiate those effects ⁴³.

In supra-segmental response, the individual with chronic pain seems to have a possible inability to increase the secretion of the hypothalamus-pituitary-adrenal axis hormones or increase the sympathetic response when dealing with physical and emotional stress. This is reflected on the increased levels of cortisol, adrenaline, noradrenaline, growth hormone (GH), and thyroid and gonadal hormones, decreasing the activity of the defense system. This model tries to explain fibromyalgia or myofascial pain; it is possible that there is an increase in the hypothalamic secretion of CRH with down regulation of receptors in the pituitary, increased levels of ACTH and low levels of cortisol, and peripheral resistance to cortisol ⁴⁴.

The hypothalamus-pituitary axis seems to interact with the painful process in several levels or stages. The absence of glucocorticoids can: 1) decrease the conversion of glutamate, an excitatory neurotransmitter, to glutamine, increasing the neurotoxicity of glutamate in the central nervous system; 2) increase the production of nerve growth factor (NGF) and substance P; and 3) increase the production of cytokines and, consequently, of NGF ⁴⁵.

Tissue and neuronal injury result in sensitization of nociceptors and facilitate peripheral and central nervous systems conduction. The study of those mechanisms may, in the future, elucidate ways to diagnose and treat acute and chronic pain syndromes.

REFERENCES

Submitted em 12 de janeiro de 2006

Accepted para publicação em 07 de setembro de 2006

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*

Received from CET/SBA da Faculdade de Medicina de Botucatu da Universidade Estadual de São Paulo (FMB – UNESP), Botucatu, SP

Publication Dates

• Publication in this collection
  19 Jan 2007
• Date of issue
  Feb 2007

History

• Accepted
  07 Sept 2006
• Received
  01 Jan 2006