whats it called when pain in your body tell your muscles to shut down

• Journal List
• Dtsch Arztebl Int
• v.105(12); 2008 Mar
• PMC2696782

Dtsch Arztebl Int. 2008 Mar; 105(12): 214–219.

Review Article

Musculus Pain: Mechanisms and Clinical Significance

Siegfried Mense

ⁱInstitut für Anatomie und Zellbiologie 3, Universität Heidelberg

Received 2007 Jul 23; Accepted 2007 December 19.

Abstract

Introduction

Musculus hurting is common, only the agreement of its causes is nonetheless patchy. This article addresses the mechanisms of some of import types of musculus pain.

Methods

Selective literature review, predominantly of information derived from neuroanatomical and electrophysiological experiments on anesthetized rats.

Results

Muscle pain is evoked by specialized nerve endings (nociceptors). Important stimuli for musculus hurting are adenosintriphosphate (ATP) and a low tissue pH. Excitation of muscle nociceptors leads to hyperexcitability of spinal sensory neurones (central sensitization). Low frequency activity in musculus nociceptors is sufficient to induce central sensitization.

Discussion

Key sensitization leads to increased excitation in the spinal cord and to referral of muscle pain. The motoneurones of a painful muscle are centrally inhibited. Muscular spasm is mostly secondary to a painful lesion in another muscle or articulation. The pain of fibromyalgia is causeless to relate to a dysfunction of key nociceptive processing. Psychosocial factors as well contribute to pain.

Keywords: muscle hurting, nociceptor, sensitization, myofascial trigger point, muscle spasm, fibromyalgia

Muscle pain is a major medical problem: in, the bulk (60% to 85%) of the population has had (nonspecific) dorsum pain of muscular origin at some time or other (lifetime prevalence) (one). Hurting evoked past myofascial trigger points has a bespeak prevalence of approximately 30% (2). More than 7% of all women aged 70 to 80 years suffer from the fibromyalgia syndrome (e1). In an Italian report, musculoskeletal pain was plant to be the near mutual reason that patients consulted a doctor (3). Thus, treating physicians should be enlightened of the mechanisms of muscle pain, insofar as they are currently understood.

This commodity provides an overview of the more than common types of muscle pain. It is not intended equally a comprehensive guide to all that is known well-nigh musculus hurting, including both basic research and clinical aspects. Psychosocial factors, in particular, are not discussed here, even though they oft play an important function in chronic pain. Considering almost of the results discussed hither were obtained in animal experiments, 1 must exist cautious in bold that they apply to human beings as well. Nevertheless, feel has shown that the pain mechanisms revealed by basic research fit in well with the corresponding clinical observations. Thus, we volition depict a number of explicit parallels between experimental findings and clinical symptoms, even though these parallels will not be entirely gratuitous of speculative content. Only a pocket-size number of therapeutic recommendations can be made on the basis of the available data. The principal purpose of this commodity is to deepen physicians' cognition of the anatomical and physiological processes underlying musculus pain.

Muscle hurting versus cutaneous pain

The scientific agreement of pain has inverse. "Pain" is no longer a unitary entity; rather, there are dissimilar types of pain that come virtually through unlike mechanisms, and that appropriately must exist treated in different means.

Muscle pain differs in many ways from hurting in the skin or viscera. These differences business not just the underlying mechanisms, simply also a number of subjective features. The main subjective differences between muscle pain and cutaneous hurting are listed in the table. I example is that pain arising in muscle tends to be referred pain more often than does pain arising in the skin. Objective differences are establish at all levels of the nervous system. Thus, ane cannot simply assume that the mechanisms of cutaneous pain are shared by muscle pain.

Table

Subjective differences between muscle pain and cutaneous pain

Muscle pain	Cutaneous hurting
Electrical nerve stimulation induces only one hurting	Electric nerve stimulation induces a showtime pain and a second pain
Poorly localizable	Well-localized
Tearing, cramping, pressing quality	Stabbing, burning, cutting quality
Marked tendency toward referral of pain	No tendency toward referral of pain
Affective aspect: difficult to tolerate	Affective attribute: easier to tolerate

Peripheral mechanisms

Muscle pain is produced past the activation of specific receptors (then-called nociceptors): these receptors are specialized for the detection of stimuli that are objectively capable of damaging tissue and that are subjectively perceived every bit painful. They consist of free nerve endings and are connected to the central nervous system (CNS) by fashion of unmyelinated (group 4) or thinly myelinated (group 3) fibers. They can be sensitized and activated by strong mechanical stimuli, such equally trauma or mechanical overloading, as well equally past endogenous inflammatory mediators including bradykinin (BK), serotonin, and prostaglandin E2 (PGE2).

Ii activating chemical substances are particularly of import for the generation of muscle pain: adenosine triphosphate (ATP) and protons (H⁺ ions). These chemical irritants activate nerve endings by binding to receptor molecules located in the membrane of the nerve ending. ATP activates musculus nociceptors mainly past bounden to the P2X3 receptor molecule, H⁺ mainly past binding to the receptor molecules TRPV1 (transient receptor potential vanilloid ane) and ASICs (acid-sensing ion channels) (4). These receptor molecules are channel proteins that span the membrane of the nervus catastrophe and mainly let Na⁺ ions to enter the neuron. These Na⁺ ions then induce neural excitation.

ATP is found in all cells of the trunk and is released whenever bodily tissues of whatsoever type are injured. Rat muscle nociceptors tin be activated past the injection of ATP in a concentration respective to that plant in muscle cells (5) (effigy 1). Weakly acidic solutions (pH half-dozen to five) are also effective activators of muscle nociceptors (half-dozen). A drop in pH is probably i of the main activators of peripheral nociceptors, every bit many painful disturbances of musculus are associated with low pH in musculus tissue. Nerve growth cistron (NGF) as well has a connectedness to muscle pain: NGF is synthesized in musculus and activates muscle nociceptors (e2). NGF synthesis is increased when a musculus is inflamed (e3).

The activation of a single muscle nociceptor by adenosine triphosphate (ATP). a) The impulse-firing action of single nociceptors was recorded from sciatic nerve filaments in anesthetized rats. The gastrocnemius-soleus (GS) muscle was dissected gratis, the receptive nervus ending was localized within it with mechanical stimuli, and the excitatory substance was injected in the vicinity of the nerve ending. b) The nociceptive catastrophe was found in the medial caput of the gastrocnemius muscle (MG; black spot). The injection of the solvent Tyrode (control substance) had no effect, merely the injection of a 7.half dozen mM solution of ATP induced activeness lasting for minutes (modified afterward [five]). RF, receptive field.

Muscle nociceptors contain neuropeptides, including substance P (SP) and calcitonin-cistron-related peptide (CGRP). These peptides are released when nervus endings are activated and induce local edema past dilating the local blood vessels and increasing their permeability. Thus, a nociceptor tin can alter the microcirculation in its firsthand neighborhood by releasing neuropeptides. Endogenous substances such every bit BK and E2 prostaglandins are released past muscle lesions of all kinds. BK is synthesized from plasma proteins by the action of the enzyme kallikrein, while prostaglandins are synthesized from arachidonic acid by the action of cyclooxygenase. These ii activating substances increase the sensitivity of nociceptors to external stimuli (peripheral sensitization).

Clinical significance

Considering ATP is released in whatever kind of tissue injury, it can be considered a universal hurting-inducing substance (7). ATP is found in particularly high concentration in muscle cells; it can cause pain in musculus trauma (eastward.g., a bruise or tear of muscle fibers) every bit well every bit in other types of pathological change in muscle (e.g., necrotizing myositis) (e4).

Acidic tissue pH is one of the main activating factors leading to muscle pain. Practically all pathological and pathophysiological changes of skeletal muscle are accompanied past a drop in pH, amidst them

• chronic ischemic states,

• tonic contractions or spasms,

• myofascial trigger points,

• (occupationally induced) postural abnormalities, and

• myositides.

The neuropeptides stored in muscle nociceptors are released not just when peripheral stimuli activate the nerve endings, just also when spinal nerves are compressed. In this type of neuropathic pain, action potentials are generated at the site of compression and spread not merely centripetally, i.e., toward the central nervous system, only likewise centrifugally, i.due east., toward the nociceptive endings, where they induce the release of vasoactive neuropeptides. In this way, neurogenic inflammation comes nigh, characterized by hyperemia, edema, and the release of inflammatory mediators (viii). The inflammatory mediators sensitize the musculus nociceptors and thereby increase neuropathic hurting.

The sensitization of the muscle nociceptors by endogenous mediators such every bit BK and PGE2 is i of the reasons why patients with muscle lesions suffer from tenderness to pressure on the muscle, and from pain on movement or exercise. It is also the reason why many types of muscle pain respond well to the administration of non-steroidal anti-inflammatory drugs (NSAID), which block prostaglandin synthesis. Sensitization manifests itself clinically in two closely related phenomena: stimuli that normally do not cause pain are perceived every bit painful (allodynia), while stimuli that are commonly painful cause more astringent pain than earlier (hyperalgesia). The principal mechanism for allodynia and hyperalgesia, however, is thought to exist located in the central nervous system.

In general, physicians should get more aware of possible muscular causes for symptoms affecting the musculoskeletal system, eastward.g., dorsum pain.

Fundamental nervous mechanisms

Mechanisms of chronification

An influx of nervous impulses from muscle nociceptors into the spinal cord increases the excitability of posterior horn neurons to a greater extent than one from cutaneous nociceptors (9). Persistent muscle nociceptor activation in experimental myositis in rats leads within a few hours to an increase in the number of neurons that tin can be activated by impulses coming from musculus (ten) (figure 2). This spread of excitation is due in part to an overexcitability of the sensory neurons of the spinal string, which, in plow, is brought about by the event of glutamate on NMDA (North-methyl-D-aspartate) receptors and of substance P on NK1 (neurokinin 1) receptors in the membranes of the spinal neurons (primal sensitization).

The machinery of generation of referred muscle pain. Normally, the L4 and L5 segments are the master area in which the GS nerve exerts its effects in the rat (GS, gastrocnemius-soleus muscle), characterized by effective synapses (gray triangles) that reliably excite the postsynaptic neurons. Local hurting arising in these segments is felt at the site of the lesion (black arrows). In animals with an inflamed GS musculus, the expanse of influence of the GS nerve was found to take expanded into the L3 segment, which contains just ineffective synapses (open up triangles) of GS afferent fibers. These synapses exercise not normally induce whatever activity potentials in the L3 neurons. In the presence of a lesion in the muscle, the muscle afferents in the L4 and L5 segments secrete substances (e.chiliad., SP = substance P, black dots) that diffuse to the L3 segment and convert the ineffective synapses in that location into constructive ones. Thus, it was newly possible for impulses from GS nociceptors (open arrows) to excite the L3 neurons, ultimately giving rise to referred pain that was felt in the distribution of the fibular nervus (lateral calf and foot).

2 main mechanisms underlie the overexcitability of spinal nociceptive neurons:

A structural alter of ion channels, rendering them more than permeable to Na⁺ and Ca2⁺, is the short-term result of an influx of nociceptive impulses into the spinal cord. Amid other effects, this causes originally ineffective ("silent" or "fallow") synapses to become effective. A silent synapse cannot generate an action potential in the postsynaptic neuron; at most, synaptic activity in it leads to merely a small excitatory post-synaptic potential. One of the mechanisms by which silent synapses become functional is an upwards shift in the membrane potential of the postsynaptic cell that is brought about past a steady stream of action potentials impinging on it. This persistent depolarization activates intracellular enzymes, which, in turn, increase the permeability of the ion channels. The result is that subthreshold potentials become larger and exceed the excitation threshold. This process tin can generate new functional connections in the CNS. Considering the membrane potential of the depolarized cell is near its excitation threshold, the cell is overexcitable and can become activated – producing pain – even in response to a weak stimulus.

A change of gene transcription in the neuronal nucleus, leading to a modification of constructed processes, causes new ion channels to be synthesized and incorporated into the nerve prison cell membrane. The long-term consequence of central sensitization is a nociceptive cell whose membrane contains a college density of ion channels that are also more than permeable to ions. This explains the hyperexcitability of the cell. Glial cells, too, particularly microglia, can contribute to the sensitization of key neurons by secreting substances such equally tumor necrosis factor a (TNF-a) (8).

It was once thought that posterior horn neurons could only be sensitized by loftier-frequency activation. This is non and then: activity potentials, or even subthreshold postsynaptic potentials, at low frequency can still suffice to make posterior horn cells overexcitable (11, 12).

Clinical significance

Tenderness to pressure and pain on move or exercise. The overexcitability of nociceptive neurons in the CNS is considered the main cause of allodynia and hyperalgesia in patients with chronic muscle hurting. The persistent depolarization of the sensitized cells has recently become the target of medications that open potasium channels and thus remove positive charge from the prison cell (e5). In this way, the membrane potential becomes increasingly negative, and thus further away from the neuron'south excitatory threshold.

The increased excitability of spinal neurons and the spread of excitation within the CNS are the commencement steps in the process of chronification of muscle pain. The endpoint of chronification consists of structural remodeling processes in the CNS that open up new pathways for nociceptive information and crusade pain to persist over the long term. Patients with chronic muscle pain are difficult to care for, because the functional and structural changes in the CNS need time to backslide. The fact that non all muscle hurting becomes chronic implies that chronification requires non only the mechanisms just discussed, merely as well other ones, e.1000., a genetic predisposition.

Referred pain arising in musculus. Pain arising in muscle is more than likely to be referred pain than hurting arising in the skin. Referred pain is pain that is felt non (only) at its site of origin, but at another site some distance abroad. A possible mechanism of referred hurting is the spread, within the spinal cord, of excitation due to the musculus lesion (nine) (figures ii and ​ iii). Equally soon every bit the excitation reaches sensory posterior horn neurons that innervate an area beyond the site of the original musculus lesion, the patient feels referred pain in that area, fifty-fifty though none of the nociceptors in it are activated (xiii).

Pain referral from a myofascial trigger point (MTrP) in the soleus muscle to the sacroiliac (SI) joint. Every bit shown in figure 2, referral of pain to the SI articulation can be explained as follows: first, nociceptors in the trigger point induce local pain. The nociceptive impulses arising from the trigger point are so carried over spinal string neurons belonging to the segments L5–S1, which are the normal relay stations for impulses from the soleus muscle. As excitation spreads in the spinal cord (in this instance, mainly in the caudal direction), the commonly ineffective connections between the soleus muscle and the neurons of the S2–S4 segments go constructive. Impulses from the trigger betoken nociceptors can now activate neurons in S2–S4 that otherwise provide sensory innervation to the SI joint. The individual therefore feels pain referred to the SI joint.

An example is shown in figure three: a stimulus delivered to the myofascial trigger bespeak (MTrP) in the soleus muscle causes only balmy local hurting, while the patient feels more severe (referred) pain in the sacroiliac articulation. No conclusive answers are yet available to the questions of why muscle pain is more than likely than cutaneous pain to be referred, why it is usually not referred to both proximal and distal sites, and why pain referral is oft discontinuous. In that location is, all the same, a well-known aperture of spinal topography betwixt the C4 and T2 dermatomes.

Changes of muscle tone equally a cause of pain

Muscle spasm can be divers as persistent, involuntary muscle wrinkle (not including spasticity, a miracle of central nervous origin). The main reason why hurting arises in muscle spasm is muscle ischemia, which leads to a drop in pH and the release of pain-producing substances such equally bradykinin, ATP, and H⁺.

The vicious-circle concept of muscle spasm – muscle hurting causes spasm, which causes more than pain, etc. – should now exist considered obsolete. Most studies have shown that muscle pain lowers the excitability of the α-motor neurons innervating the painful muscle (14) (a "pain adaptation" model) (fifteen).

Clinical significance

Muscle spasm can be precipitated by, among other things, pain in another muscle. Thus, a spasm-like increase EMG activity in the trapezius muscle has been described in response to painful stimulation of the biceps brachii musculus (sixteen). Another source of musculus spasms is pathological changes in a neighboring joint. These sources of hurting must be deliberately sought.

Myofascial trigger points

Myofascial trigger points (MTrP's) are palpable, punctate areas of hardening in the muscle tissue that are painful on movement and palpation (17). Light-microscopic studies performed many years ago already revealed and then-chosen contraction knots within MTrP'south (18): these are local thickenings of private muscle fibers brought about by the contraction of a small number of sarcomeres.

In a widespread hypothesis on the origin of MTrP'due south (xix), it is supposed that a muscular lesion damages the neuromuscular endplate so that it secretes an excessive amount of acetylcholine. The ensuing depolarization of the muscle cell membrane produces a contraction knot that compresses the neighboring capillaries, causing local ischemia. Ischemia, in turn, leads to the release of substances into the tissue that sensitize nociceptors, bookkeeping for the tenderness of MTrP's to pressure level. Substances of this type have been constitute to be present within the MTrP's of these patients (20). This supposed machinery leaves many questions unanswered only is currently the only comprehensive hypothesis on the origin of MTrP'southward.

Clinical significance

Patients with MTrP'south oft have hurting in three locations:

• at the site of the MTrP itself,

• at the origin or insertion of the afflicted muscle, because of pulling by the muscle fibers that have been stretched by the contraction knots,

• and referred pain outside the MTrP (figure three).

Considering the MTrP is cut off from its blood supply by compression of the local microcirculation, oral NSAID'due south are not very effective against TrP hurting. Therapeutic injections into the trigger betoken presumably work by diluting the sensitizing substances that are present here (among other mechanisms), as normal saline injections have been found to be but equally effective as local anesthetic injections (13).

The referred symptoms associated with an MTrP often lead patients to localize their pain incorrectly. In such cases, the doc must deliberately search for the actual source of the pain past palpation of the muscle, and then care for information technology appropriately.

Descending nociceptive inhibition and the fibromyalgia syndrome

An important symptom of the fibromyalgia syndrome (FMS) is generalized hurting that is mainly felt in the musculature (21). Two main models have been proposed to account for generalized muscle hurting:

• An increased influx of nociceptive stimulation into muscle nociceptors leads to sensitization of neurons in the central nervous system, and thereby to generalized hypersensitivity to pain (22). In the muscles of FMS patients, however, merely nonspecific changes have been found, which in all likelihood exercise not excite the musculus nociceptors. It remains an open question whether the changes in musculus histology that were seen in one study (e6) accept any relevance to the pain of FMS.

• The descending pain-modulating systems (i.e., pain-inhibiting and pain-promoting systems) are dysfunctional. The most of import of these is the pain-inhibiting system that normally tonically dampens the activeness of spinothalamic tract neurons (23), which constitute the main spinal nociceptive pathway. The neurons of origin of this pain-inhibiting organisation lie in the midbrain. The neural impulses of this arrangement travel, by way of a relay station in the medulla, to the nociceptive cells of the spinal cord, where the actual inhibition takes place. The activeness of the descending organization is influenced by connections to the prefrontal cortex, the hypothalamus, and the limbic system. The descending system employs endogenous opioids also as serotonin and noradrenaline as neurotransmitters (24). The descending hurting-inhibiting arrangement exerts a particularly strong effect on neurons that mediate muscle hurting (e7); thus, dysfunction of this organization would exist expected mainly to cause muscle pain.

Clinical significance

The model of increased peripheral nociceptive activity leading to cardinal sensitization can explain cases in which a local trauma, eastward.g., a whiplash injury of the cervical spine (e8), develops into a generalized fibromyalgia syndrome.

Many authors favor a chief cause in the central nervous system in the form of a dysfunctional processing of nociceptive information. The dysfunction might consist, for instance, of an insufficient degree of activity in the descending pain-inhibiting pathways, or of excessive activity in the descending pain-promoting pathways (24). Connections to the limbic system explicate the fact that psychosocial influences play a major office in the hurting of FMS. If the descending inhibition of pain is bereft, i.e., if the neurons of the spinothalamic tract are disinhibited, then pain may arise fifty-fifty in the absence of a painful stimulus in the periphery.

Clinical examination reveals sites of excessive sensitivity to palpation (tender points, TeP), at which balmy externally practical pressure causes pain. Many of these TeP'southward are located at the myotendinous junction, rather than near the belly of the muscle, where MTrP's are more likely to exist found. These TeP'south are non associated with any local pathological changes (as far as is known) only are rather the expression of a generalized hypersensitivity to hurting. FMS patients have a low pain threshold in the pare and subcutaneous tissue every bit well as in musculus (25).

Dysfunction of the descending pain-inhibiting system is suggested by the fact that the hurting of FMS ordinarily does not reply to morphine, which exerts its analgesic event mainly by activating the hurting-inhibiting pathways.

Acknowledgments

Translated from the original German language by Ethan Taub, M.D.

Footnotes

Conflict of interest statement

The author states that he has no conflict of interest as defined by the guidelines of the International Committee of Medical Journal Editors.

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