Functional Anatomy of Muscle – Muscle, Nociceptors and Afferent Fibers

Svært mye interessant om nervesystemets rolle i muskler og smerte.

Spesielt at det er ingen frie nerveender i muskelcellene, men bare i blodkarene i musklene. Derfor reagerer vi med smerte på betennelser og lav pH i blodet, mens trykksensitiviteten kun sitter i huden.

Den nevner at pH sensibiliteten er den viktigste smertebidraget fordi pH synker i de fleste patologiske tilstander, f.eks. hard trening eller skade.

Den nevner at det er mer SP (Substans P, som er relatert til smerte) i huden enn i muskler.

Nevner at frie nerveender ikke går til kapillærer eller muskelceller, bare til arterioler og venuler.

Nevner også innervering av bindevev, og at dette feltet foreløpig er lite studert og oversett. Spesielt viser de til at Toracolumbar Facia (i korsryggen) har størst innervasjon av C-fiber nociceptorer(som inneholder SP) under huden, og litt i multifidene.

En nociceptor er ikke bare en passiv mottaker av impulser, men er også en aktiv deltaker i vevets tilstand når det gjelder betennelser og blodsirkulasjon for de sender nevropetider ut fra doresalhornet til vevet (antidromiske impulser). Altså motsatt vei av reseptor-signalretningen.

CGRP virker vasodilerende, mens SP gjør at blodkarveggenes permeabilitet øker. Når permeabiliteten øker siver det ut proteiner og stoffer som egentlig ikke skal være i vevet, og da økes betennelser og immunsystemets aktivitet. Så det er SP vi ønsker å dempe først og fremst.

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The predominant location of free nerve endings supplied by group IV fibers was the adventitia of arterioles and venules. Surprisingly, muscle fibers themselves did not receive direct innervation by free nerve endings. Group III afferents generated not only free nerve endings but also paciniform corpuscles, whereas group IV fibers terminated exclusively in free nerve endings.The high sensitivity of the free nerve endings to chemical stimuli, particularly to those accompanying inflammatory lesions or disturbances of the microcirculation, may be related to their location on or in the walls of the blood vessels. The finding that the muscle fibers proper are not supplied by free nerve endings (Reinert et al. 1998) may relate to the clinical experience that muscle cell death is usually not painful, at least not if it occurs slowly, as for instance during muscular dystrophy, polymyositis, or dermatomyositis. A different situation is tearing of a muscle fiber bundle, which can be extremely painful. In this condi- tion, many muscle cells are destroyed simultaneously and release their contents (e.g., K+ ions and ATP) in the interstitial space, from where they can diffuse to the next nociceptive endings.
In skeletal muscle, the free nerve endings appear to be distributed quite evenly in the proximodistal direction. At least, in a quantitative evaluation of the inner- vation density by neuropeptide-(SP- and CGRP-) containing fibers, no difference between the proximal and distal portions of the rat gastrocnemius–soleus (GS) muscle was found (Reinert et al. 1998). Therefore, a higher innervation density at the transition zone between muscle and tendon is not a probable explanation for the frequent pain in this region.

However, in the same study the nerve fiber density in the peritendineum (the connective tissue around a tendon) of the rat calcaneal tendon was found to be several times higher than that in the GS muscle. In contrast, the collagen fiber bundles of the tendon tissue proper were almost free of free nerve endings. The high fiber density in the peritendineum may explain the high prevalence of tenderness or pain in the tissue around the tendon and the insertion site. The scarcity of nerve endings in the center of the tendon may relate to the clinical observation that (incomplete) ruptures of the tendon may occur without pain.

Judging from their respon- siveness to pain-producing agents, the following receptor molecules are likely to be relevant for muscle pain and tenderness (Mense and Meyer 1985; Caterina and David 1999; McCleskey and Gold 1999; Mense 2007):

  • Bradykinin (BKN) receptors (B1 and B2). BKN is cleaved from blood plasma proteins when a blood vessel breaks or increases its permeability so that plasma proteins enter the interstitial space. In intact tissue, BKN excites nerve endings by the activation of the BKN receptor molecule B2, whereas under pathological conditions (e.g., inflammation) the receptor B1 is the predominant one (Perkins and Kelly 1993; for a review of receptor molecules mediating the effects of classic inflammatory (pain-producing or algesic) substances, see Kumazawa 1996).
  • Serotonin receptors (particularly 5-HT3). Serotonin (5-hydroxytryptamin, 5-HT) is released from blood platelets during blood clotting. The stimulating effects of serotonin on nociceptive terminals in the body periphery are predomi- nantly mediated by the 5-HT3 receptor (at present, more than 15 different 5-HT receptors are known in the CNS). The serotonin concentrations released in the tissue are usually not sufficient to excite nociceptors directly, but they can sen- sitize them, i.e., make them more sensitive to other pain-producing agents such as BKN.
  • Prostaglandins, particularly prostaglandin E2 (PGE2). Prostaglandins (PGs) are released in a pathologically altered muscle by the enzymatic action of cycloox- igenases. PGE2 binds to a G protein-coupled prostanoid receptor (EP2) in the membrane of the nociceptive ending. Similarly to serotonin, PGE2 sensitizes nociceptors rather than exciting them under (patho)physiological circumstances (Mense 1981).
  • Acid-sensing ion channels (ASICs). ASICs constitute a family of receptor molecules that are sensitive to a drop in pH and open at various pH values. The channel proteins react already to small pH changes, for instance from pH 7.4 to 7.1. This receptor family (for instance ASIC1 and ASIC3) is particularly impor- tant for muscle pain, because almost all pathologic changes in muscle are accom- panied by a drop in tissue pH, e.g., exhausting exercise, ischemia, and inflammation (Immke and McCleskey 2003). In these conditions, the pH of the muscle tissue can drop to 5–6. The proton-sensitive nociceptors may also be of importance for the induction of chronic muscle pain. Repeated intramuscular injections of acidic solutions have been reported to induce a long-lasting hyper- algesia (Sluka et al. 2001).
  • P2X3 receptors. This receptor is a subtype of the purinergic receptors that are activated by ATP and its derivatives (Burnstock 2007; Ding et al. 2000). ATP is the energy-carrying molecule in all cells of the body; accordingly, it is present in every tissue cell. It is released from all tissues during trauma and other pathologic changes that are associated with cell death. For this reason, ATP has been considered a general signal substance for tissue trauma and pain (Cook and McCleskey 2002). ATP is particularly important for muscle pain, because it is present in muscle cells in high concentration (Stewart et al. 1994). When injected into human muscle, ATP causes pain (Mo ̈rk et al. 2003).
  • Transient receptor potential receptor subtype 1 (TRPV1) formerly called VR1. This receptor is one of the most important molecules for the induction of pain. The natural stimulant for the TRPV1 receptor is Capsaicin, the active ingredient of chilli peppers (Caterina and Julius 2001). The receptor is also sensitive to an increase in H+-concentration and to heat, with a threshold of approximately 39C. Its endoge- nous ligands are H+-ions.
  • Other TRP receptors. TRPV4 is a mechanosensitive ion channel that is sensitive to both weak and strong (noxious) intensities of local pressure (Liedtke 2005). It may be the receptor for mediating pain evoked by pinching and squeezing.
  • Tyrosine kinase A (TrkA) receptor. The ligand of this receptor is NGF (Caterina and David 1999). NGF is well-known for its sensitizing action on nociceptors in the body periphery and neurons in the CNS; it is synthesized in muscle, and its synthesis is increased during pathophysiological changes of the muscle (e.g., inflammation, Menetrey et al. 2000; Pezet and McMahon 2006).
  • Glutamate receptors. There is evidence indicating that the NMDA receptor (one of the receptors for glutamate) is present on nociceptive endings in masticatory muscles. Injections of glutamate into the masseter muscle in human subjects induced a reduction in pressure pain threshold which was attenuated by coinjection with ketamine, an NMDA receptor antagonist (Cairns et al. 2006).
Substances exciting muscle nociceptors independent of membrane receptors.
  • Hypertonic saline: injections of NaCl solutions (4.5–6.0%) have long been and still are used to elicit pain from deep somatic tissues (Kellgren 1938; for review, see Graven-Nielsen 2006).
  • Potassium ions: The most likely explanation for the excitatory action of high concentrations of extracellular potassium ions is a depolarization of the membrane potential due to a reduction of the inside–outside potassium gradient (usually the potassium concentration inside the axon is much higher).

DRG cells projecting in a cutaneous nerve have been reported to contain SP, CGRP, and somatostatin (SOM).

In comparison to skin nerves, muscle nerves appear to contain less SP. This finding makes sense, because the vasodilatation and plasma extrava- sation caused by the release of SP and CGRP from free nerve endings (see below) would be dangerous for skeletal muscles, since many of them are surrounded by a tight fascia. Therefore, an SP-induced muscle edema would result in a high increase in interstitial pressure, and could cause muscle necrosis.

In a study on functionally identified DRG cells employing a combination of electrophysiological and immunohistochemical techniques, Lawson et al.(1997) reported that cells terminating in cutaneous nociceptive endings showed a strong tendency to express SP, particularly if they had a slow conduction velocity or a small soma in the DRG. 

The peptides are synthesized in the somas of the DRG or in ganglion cells of cranial nerves. They are transported to both the central and the peripheral terminal of the primary afferent unit.

In a quantitative evaluation of neuropeptide-containing free nerve endings and preterminal axons (both characterized by varicosities) in the GS muscle of the rat, most endings were found around small blood vessels (arterioles or venules), whereas capillaries and the muscle cells proper were not contacted by these end- ings.

Efferent or motor fibers conduct action potentials from the CNS to the periphery; their soma is located in the spinal cord or brainstem and the fibers leave the CNS via the ventral root or cranial nerve motor roots. An exception are postganglionic sympathetic fibers whose cell bodies are mostly located in the sympathetic trunk (e.g., vasomotor fibers that constrict blood vessels).

The nerve to a locomotor muscle in the cat (the lateral GS) is composed of approximately one-third myelinated (720) and two-thirds unmyelinated (2,480) fibers (Table 2.2; Mitchell and Schmidt 1983; Stacey 1969). Nearly one quarter of the myelinated (group III) fibers had nociceptive properties in neurophysio- logical experiments (Mense and Meyer 1985). Of the unmyelinated fibers, 50% are sensory (group IV), and of these, approximately 55% have been found to be nociceptive in the rat (Hoheisel et al. 2005).

Data obtained from one muscle nerve cannot be transferred directly to other muscle nerves, because considerable differences exist between different muscles. For instance, neck muscle nerves of the cat contain unusually high numbers of sensory group III receptors (Abrahams et al. 1984). One possible explanation for these differences is that the muscles have different functions and environmental conditions: in contrast to the neck muscles, which must register the orientation of the head in relation to the body in fine detail, the locomotor hindlimb muscles often have to contract with maximal strength and under ischemic conditions.

In addition to nociceptors, there are other muscle receptors whose function is essential for the understanding of muscle pain:

  • Muscle spindles are complex receptive structures that consist of several specialized muscle fibers (the so-called intrafusal muscle fibers; the name is derived from their location inside the spindle-shaped connective tissue sheath. Accordingly, all the “normal” muscle fibers outside the spindle are “extrafusal” fibers). Muscle spindles measure the length and the rate of length changes of the muscle, i.e., their discharge rate increases with increasing muscle length and with increasing velocity of the length change.
  • Golgi (tendon) organs measure the tension of the muscle. They are arranged in series with the extrafusal muscle fibers; their location is the transition zone between muscle and tendon. The supplying fiber is the Ib afferent, whose structure is identical to the Ia fiber (thick myelin sheath and high conduction velocity). The receptor has a much simpler structure than the muscle spindle; it consists of receptive endings that are interwoven between the collagen fiber bundles of the tendon.
  • Muscle spindles and Golgi organs are proprioceptors, i.e., they measure the internal state of the body.
  • Pacinian corpuscles (PC) and paciniform corpuscles. These receptors do not respond to static pressure; they require dynamically changing mechanical stimuli, and are best excited by vibrations of relatively high frequency (close to 300 Hz; Kandel et al. 2000). The receptive ending is formed like a rod, and covered by several concentric membranes which give the receptor an onion-like appearance in cross-sections.

At present, little information is available about the innervation of fascia. This is an important gap in our knowledge, because fascia is an important component of the musculoskeletal system and likely to contribute to many forms of pain that are subsumed under the label “muscle” pain. One example is low back pain: The thoracolumbar fascia (TF) plays an essential role in body posture and trunk move- ments (Bogduk and Macintosh 1984). It is not only a passive transmitter of mechanical forces of the low back and abdominal muscles but also contractile by itself (Schleip et al. 2005).

In the connective tissue around the superficial lamina of the TF we found many CGRP- and SP-containing free nerve endings. The majority of the fibers were located in the subcutaneous layer, as well as between the fascia and the surface of the multifidus muscle (Fig. 2.8). The SP-positive endings are of particular interest, because they are thought to be nociceptors.
The loose connective tissue around the TF is probably deformed during any trunk movement, and therefore the free nerve endings are strategically situated to sense any disorders in these movements. It is conceivable that overload of the fascia puts mechanical stress and irritation on the endings, and thus may contribute to low back pain.
SP then releases histamine from mast cells, and together with CGRP these agents cause vasodilatation and an increase in vascular permeability of the blood vessels around the active ending. The result is a shift of blood plasma from the intravascular to the interstitial space. Outside the blood vessel, BKN is cleaved from the plasma protein kallidin, serotonin (5-HT) is set free from platelets, and PGs (particularly PGE2) from endothelial and other tissue cells. All these substances sensitize nociceptors. Thus, the main tissue alteration induced by a nondestructive noxious mechanical stimulus is a localized region of vasodilatation, edema, and sensitized nociceptors.
A nociceptor is not a passive sensor of tissue-threatening stimuli; it actively influences the microcirculation and chemical composition of the intersti- tial space around it.
If a noxious stimulus activates only one part of the ending, the action potentials originating in that region of the ending can invade antidromically (against the normal direction of propagation) those branches of the ending that were not excited by the stimulus. These antidromic action potentials release neuropeptides from the unstimulated branches. The whole process is called the axon reflex.  It is assumed to be the reason for the visible wheal and flare around a cutaneous lesion.

The vascular permeability is increased mainly by SP (and by the neurokinins A and B; Gamse and Saria 1985), whereas CGRP is assumed to act primarily as a vasodilator. There is evidence showing that CGRP enhances the plasma extravasation induced by SP and neurokinins A and B, but reduces the vasodilatory action of SP by desensitizing muscle arterioles to the peptide (O ̈ hle ́n et al. 1988).

The area of wheal and flare after a localized damage to the skin – for instance around a needle prick – could be an indicator of the extent of the excited nocicep- tive ending.

The size of the receptive fields (RFs) of cutaneous polymodal nociceptors was found to be less than 2 mm in cat (Bessou and Perl 1969) and 6–32 mm in rabbit (Kenins 1988). A receptive field is that region of the body from which a receptive ending (or a central sensory neuron) can be excited. The above figures are larger than the reported length of the branches of a nociceptor ending (a few hundred mm; Stacey 1969).

The release of SP, CGRP, neurokinin A, and other agents from nociceptors is the central factor in the cascade of events that lead to neurogenic inflammation in the periphery (Lembeck and Holzer 1979). Neurogenic inflammation is characterized by tissue edema and infiltration by immune cells, i.e., it exhibits the major histo- logical signs of a (sterile) inflammation. It develops whenever action potentials are generated not at the receptive ending but somewhere along the course of primary afferent units (spinal nerve or dorsal root). The action potentials propagate both to the CNS (causing pain) and to the peripheral ending (causing release of neuropep- tides and neurogenic inflammation). The published data indicate that vasodilatation can be elicited by antidromic stimulation of both Ad- and C fibers, but increase in vascular permeability and plasma extravasation by stimulation of C fibers only.

Neuropathies and radiculopathies and other pathological conditions that are asso- ciated with antidromic activity in sensory nerve fibers are examples of such events (Marchand et al. 2005). Neurogenic inflammation is likely to increase the dysesthe- sia and pain of patients suffering from neuropathies.

Inflammatory disorders are usually accompanied by sensitization of peri- pheral nociceptors, which is one source of inflammatory pain (for details, see Chap. 3). 

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