Short-term swimming exercise attenuates the sensitization of dorsal horn neurons in rats with NGF-induced low back pain.

BACKGROUND: Physical exercise has been shown to be an effective therapy for non-specific low back pain. The study investigated if swimming exercise is a means to reduce the spinal sensitization in an animal model of non-specific low back pain. METHODS: In deeply anesthetized rats, dorsal horn neurons were recorded in spinal segment L2. To induce sensitization of dorsal horn neurons, two injections of nerve growth factor were made into the lumbar multifidus muscle at an interval of 5 days. Swimming exercise for 30 min was performed on the 5 days between both NGF injections. A control group received the NGF injections without exercise treatment. RESULTS: Swimming exercise caused a significant decrease in the NGF-induced hyperexcitability of dorsal horn neurons. Compared to control, the proportion of neurons with input from deep somatic tissues and of convergent neurons with input from at least two types of different tissues decreased significantly (50% vs. 25% and 37% vs. 15%; both p < 0.05). Swimming exercise also reduced the NGF-induced increase in neuronal resting activity. Both the proportion of active neurons and the mean discharge frequency of all neurons decreased significantly (60%, 76.3 ± 23.1 imp/min; vs. 25%, 51.7 ± 35.1 imp/min; both p < 0.01). CONCLUSIONS: In our animal model of low back pain, short-term swimming exercise effectively reduced the latent sensitization of spinal dorsal horn neurons. Swimming exercise decreased the hyperexcitability of the neurons to low back input and lowered the resting activity of sensitized neurons. SIGNIFICANCE: Physical exercise is a common treatment for low back pain. The possible mechanisms underlying the effects of exercise are probably multifold. This work shows that swimming exercise prevents sensitization of dorsal horn neurons, which may be one mechanism for the positive effects of exercise.

Innervation changes induced by inflammation of the rat thoracolumbar fascia.

Recently, the fascia innervation has become an important issue, particularly the existence of nociceptive fibers. Fascia can be a source of pain in several disorders such as fasciitis and non-specific low back pain. However, nothing is known about possible changes of the fascia innervation under pathological circumstances. This question is important, because theoretically pain from the fascia cannot only be due to increased nociceptor discharges, but also to a denser innervation of the fascia by nociceptive endings. In this histological study, an inflammation was induced in the thoracolumbar fascia (TLF) of rats and the innervation by various fiber types compared between the inflamed and intact TLF. Although the TLF is generally considered to have proprioceptive functions, no corpuscular proprioceptors (Pacini and Ruffini corpuscles) were found. To obtain quantitative data, the length of fibers and free nerve endings were determined in the three layers of the rat TLF: inner layer (IL, adjacent to the multifidus muscle), middle layer (ML) and outer layer (OL). The main results were that the overall innervation density showed little change; however, there were significant changes in some of the layers. The innervation density was significantly decreased in the OL, but this change was partly compensated for by an increase in the IL. The density of substance P (SP)-positive - presumably nociceptive - fibers was significantly increased. In contrast, the postganglionic sympathetic fibers were significantly decreased. In conclusion, the inflamed TLF showed an increase of presumably nociceptive fibers, which may explain the pain from a pathologically altered fascia. The meaning of the decreased innervation by sympathetic fibers is obscure at present. The lack of proprioceptive corpuscular receptors within the TLF does not preclude its role as a proprioceptive structure, because some of the free nerve endings may function as proprioceptors.

Immobilization stress sensitizes rat dorsal horn neurons having input from the low back.

BACKGROUND: Stress is known to promote several forms of muscle pain including non-specific low back pain. However, the question if stress alone activates nociceptive central neurons has not been studied systematically. Here, we investigated the influence of repeated immobilization stress on dorsal horn neurons and behaviour in the rat. METHODS: The stress consisted of immobilization in a narrow tube for 1 h on 12 days. Single dorsal horn neurons were recorded with microelectrodes introduced into the spinal segment L2. In this segment, about 14% of the neurons responded to mechanical stimulation of the subcutaneous soft tissues of the low back in naïve rats. The neurons often behaved like wide dynamic range cells in that they had a low mechanical threshold and showed graded responses to noxious stimuli. RESULTS: The stress-induced changes in neuronal response behaviour were (1) appearance of new receptive fields in the deep tissues of the hindlimb, (2) increased input from deep soft tissues, but unchanged input from the skin and (3) significant increase in resting activity. Surprisingly, the pressure-pain threshold of the low back remained unchanged, although dorsal horn neurons were sensitized. In the open field test, the rats showed signs of increased anxiety. CONCLUSIONS: This study shows that stress alone is sufficient to sensitize dorsal horn neurons. The data may explain the enhanced pain low back patients report when they are under stress. The increased resting discharge may lead to spontaneous pain.

Inflammation of the thoracolumbar fascia excites and sensitizes rat dorsal horn neurons.

BACKGROUND: Recent data show that the thoracolumbar fascia can be a source of pain. However, the spinal neuronal mechanisms underlying pain from a pathologically altered fascia are unknown. The present study aimed at finding out how dorsal horn neurons react to input from a chronically inflamed thoracolumbar fascia. METHODS: Recordings from rat dorsal horn neurons were made in the spinal segment L3. Twelve days before the recordings, the thoracolumbar fascia was inflamed by injection of complete Freund's adjuvant. Control animals received an injection of isotonic saline. In addition, behavioural experiments were carried out. RESULTS: Neurons in the spinal segment L3 do not normally receive input from the fascia, but 11.1% of the neurons did when the fascia was inflamed. Compared with control, the proportion of neurons having input from all deep somatic tissues rose from 10.8% to 33.3% (p < 0.02). Moreover, many neurons acquired new deep receptive fields, most of which were located in the hindlimb (p < 0.04). Surprisingly, the pressure pain threshold of the inflamed rats did not change, but they showed a reduction in exploratory activity. CONCLUSIONS: One of the prominent findings was the appearance of new receptive fields in deep tissues of the hindlimb. Together with the expansion of the spinal target region of fascia afferents into the segment L3, the appearance of new receptive fields is a possible explanation for the spread of pain in patients with non-specific low back pain.

Sensory innervation of the thoracolumbar fascia in rats and humans.

The available data on the innervation of the thoracolumbar fascia (TLF) are inconsistent and partly contradictory. Therefore, the role of the fascia as a potential source of pain in the low back is difficult to assess. In the present study, a quantitative evaluation of calcitonin gene-related peptide (CGRP) and substance P (SP)-containing free nerve endings was performed in the rat TLF. A preliminary non-quantitative evaluation was also performed in specimens of the human TLF. The data show that the TLF is a densely innervated tissue with marked differences in the distribution of the nerve endings over the fascial layers. In the rat, we distinguished three layers: (1) Outer layer (transversely oriented collagen fibers adjacent to the subcutaneous tissue), (2) middle layer (massive collagen fiber bundles oriented obliquely to the animal's long axis), and (3) inner layer (loose connective tissue covering the paraspinal muscles). The subcutaneous tissue and the outer layer showed a particularly dense innervation with sensory fibers. SP-positive free nerve endings-which are assumed to be nociceptive-were exclusively found in these layers. Because of its dense sensory innervation, including presumably nociceptive fibers, the TLF may play an important role in low back pain.

[Differences between myofascial trigger points and tender points]. / Unterschiede zwischen myofazialen Triggerpunkten und "tender points".

The article describes and compares the characteristics of myofascial trigger points (MTrPs) of the myofascial pain syndrome and the tender points (TePs) of the fibromyalgia syndrome. Many statements are hypothetical, because not all aspects of the disorders have been clarified in solid studies. Signs and symptoms of MTrPs: (1) palpable nodule, often located close to the muscle belly, (2) often single, (3) allodynia and hyperalgesia at the MTrP, (4) referral of the MTrP pain, (5) normal pain sensitivity outside the MTrPs, (6) local twitch response, (7) local contracture in biopsy material, (8) peripheral mechanism probable. Signs and symptoms of TePs: (1) no palpable nodule, (2) location often close to the muscle attachments, (3) multiple by definition, (4) allodynia and hyperalgesia also outside the TePs, (5) enhanced pain under psychic stress, (6) unspecific histological changes in biopsy material, (7) central nervous mechanism probable. The multitude of differences speak against a common aetiology and pathophysiology.

Algesic agents exciting muscle nociceptors.

Morphologically, muscle nociceptors are free nerve endings connected to the CNS by thin myelinated (group III) or unmyelinated (group IV) afferent fibers. Not all of these endings are nociceptive; approximately 40% have a low mechanical threshold and likely fulfill non-nociceptive functions. Two chemical stimuli are particularly relevant as causes of muscle pain. The first is a drop in tissue pH, i.e. an increase in proton (H+) concentration. A large number of painful patho(physio)logical alterations of muscle tissue are associated with an acidic interstitial pH (e.g. tonic contractions, spasm, inflammation). The second important cause of muscle pain is a release of adenosine triphosphate (ATP). ATP is present in all body cells, but in muscle its concentration is particularly high. Any damage of muscle cells (trauma, necrotic myositis) is accompanied by a release of ATP from the cells. Therefore, ATP is considered a general pain stimulus by some. ATP and protons are relatively specific stimuli for muscle pain; in cutaneous pain they play a less important role. The numerous agents that are released in pathologically altered muscle include substances that desensitize mechanosensitive group IV receptors. Capsaicin has a long-lasting desensitizing action, brain-derived neurotrophic factor, and tumor necrosis factor-alpha, a short-lasting one. Most of the agents exciting group IV units (e.g. low pH, ATP, capsaicin) activate not only nociceptive endings but also non-nociceptive ones. The only substance encountered that excites exclusively nociceptive group IV receptors is nerve growth factor (NGF). In rat muscle chronically inflamed with complete Freund's adjuvant, most group IV endings are sensitized to mechanical (and to some) chemical stimuli. However, stimulants such as ATP, NGF, and solutions of low pH were found to be less effective in inflamed muscle. A possible explanation for this surprising finding is that in inflamed muscle the concentrations of ATP and NGF and H+ are increased. Therefore, experimental administration of these agents is a less effective stimulus.

Influence of a chronic myositis on rat spinal field potentials evoked by TTX-resistant unmyelinated skin and muscle afferents.

A recent study of our group has shown that in the segments L4 and L5 of the rat, the synaptic field potentials (SFPs) evoked by tetrodotoxin-resistant (TTX-r, presumably nociceptive) muscle afferents differ in size and peak location from those of cutaneous afferents from the same body region [Lambertz D, Hoheisel U, Mense S. Distribution of synaptic field potentials induced by TTX-resistant skin and muscle afferents in rat segment L4 and L5. Neurosci Lett 2006;409:14-8]. Here, we investigated the influence of a muscle inflammation on the distribution of SFPs of TTX-r afferent fibres from muscle and skin in the thoracic and lumbar spinal cord. During a TTX block of the dorsal roots L3-L6, a skin nerve (sural, SU) or a muscle nerve (gastrocnemius-soleus, GS) were electrically stimulated at an intensity supramaximal for unmyelinated afferents and the SFPs recorded with tungsten microelectrodes. In control (non-inflamed) rats, the largest SFPs evoked by TTX-r GS afferents were recorded in laminae IV-VI with a maximum in segment L4, whereas the largest SU-induced SFPs were more superficially located with a maximum in L3. In chronic myositis animals, SFPs induced by GS TTX-r fibres exhibited significant decreases in lamina IV-VI of Th 12 and L5 as well as in lamina VII of L5. In contrast, SFPs evoked by SU TTX-r afferents showed significant increases in lamina IV-VI in L1 and in lamina VII in L4. The results demonstrate that a chronic myositis has a strong influence also on the synaptic effects of nociceptive afferents from the skin, which may explain the subjective cutaneous sensations during a pathological alteration of muscle.

Distribution of synaptic field potentials induced by TTX-resistant skin and muscle afferents in rat spinal segments L4 and L5.

Previous results from our group and others showed that skin and muscle afferents are equipped with tetrodotoxin-resistant (TTX-r) channels. The great majority of the TTX-r fibres are unmyelinated (C or group IV) and are assumed to have nociceptive functions. Therefore, a block of the TTX-sensitive (TTX-s) fibres offers the possibility to study reactions of central nervous neurones to a purely nociceptive input. The present study compared spinal synaptic field potentials (SFPs) evoked by electrical stimulation of TTX-r afferent fibres from skin and muscle at various depths of the spinal segments L4 and L5 in the rat. Cutaneous input was produced by stimulation of the sural nerve (SU), input from muscle by stimulation of the gastrocnemius-soleus nerves (GS). To block the (non-nociceptive) TTX-s afferents, a pool containing TTX (concentration 1microM) was built around the dorsal roots L3-L6. As a measure of synaptic activity, the area of averaged SFPs was determined. After TTX application, the SFPs of fast conducting myelinated afferent fibres vanished completely. Simultaneously, the size of the potentials evoked by electrical stimulation of slowly conducting TTX-r skin and muscle afferents increased significantly. The field potentials of TTX-r GS afferents had a maximum in laminae IV-VI of the dorsal horn, whereas the SFPs induced by SU stimulation were more evenly distributed over all laminae. The results are a further indication that nociceptive input from skin and muscle is differently processed at the spinal level.

Gene expression profiling reveals the profound upregulation of hypoxia-responsive genes in primary human astrocytes.

Oxygen is vital for the development and survival of mammals. In response to hypoxia, the brain initiates numerous adaptive responses at the organ level as well as at the molecular and cellular levels, including the alteration of gene expression. Astrocytes play critical roles in the proper functioning of the brain; thus the manner in which astrocytes respond to hypoxia is likely important in determining the outcome of brain hypoxia. Here, we used microarray gene expression profiling and data-analysis algorithms to identify and analyze hypoxia-responsive genes in primary human astrocytes. We also compared gene expression patterns in astrocytes with those in human HeLa cells and pulmonary artery endothelial cells (ECs). Remarkably, in astrocytes, five times as many genes were induced as suppressed, whereas in HeLa and pulmonary ECs, as many as or more genes were suppressed than induced. More genes encoding hypoxia-inducible functions, such as glycolytic enzymes and angiogenic growth factors, were strongly induced in astrocytes compared with HeLa cells. Furthermore, gene ontology and computational algorithms revealed that many target genes of the EGF and insulin signaling pathways and the transcriptional regulators Myc, Jun, and p53 were selectively altered by hypoxia in astrocytes. Indeed, Western blot analysis confirmed that two major signal transducers mediating insulin and EGF action, Akt and MEK1/2, were activated by hypoxia in astrocytes. These results provide a global view of the signaling and regulatory network mediating oxygen regulation in human astrocytes.

The influence of the 5-HT3 receptor antagonist tropisetron on pain in fibromyalgia: a functional magnetic resonance imaging pilot study.

OBJECTIVE: Central pain processing is altered in patients with fibromyalgia syndrome (FMS). The serotonin metabolism, especially the 5-HT3 receptor, seems to play an important role. METHODS: We investigated the effect of the local injection of the 5-HT3 receptor antagonist tropisetron on the perception and central processing of pain in FMS patients using painful mechanical stimulation and functional magnetic resonance imaging (fMRI) within the framework of a pre-/posttreatment double-blind design. RESULTS: In the contralateral primary somatosensory cortex, contralateral posterior insula, and anterior cingulate cortex, we found that the activation was significantly reduced after treatment. On average, patients rated the stimulation-induced pain intensity as stronger in the session after treatment compared to before treatment, although the individual data revealed a heterogeneous pattern. All patients showed sensitisation during the painful stimulation, which was not influenced by the treatment. CONCLUSIONS: Both the sensory-discriminative and motivational-affective components of pain as measured by fMRI were altered by tropisetron.

[Functional neuroanatomy for pain stimuli. Reception, transmission, and processing]. / Funktionelle Neuroanatomie und Schmerzreize. Aufnahme, Weiterleitung und Verarbeitung.

This short overview presents some of the current neuroanatomical knowledge concerning pathways and nuclei mediating pain sensations. The axonal membrane of the nociceptor is equipped with a multitude of receptor molecules that specifically bind pain-producing and sensitizing substances. Recently, adenosine triphosphate and protons have attracted much interest. The different nociceptor types are probably characterized by different sets of receptor molecules in the membrane of the nociceptive ending. Nociceptive cells are present in the superficial laminae and the neck of the dorsal horn. The cells in the former region include nociceptive-specific ones that receive input from nociceptors exclusively, whereas in the neck of the dorsal horn a convergent input from nociceptive and non-nociceptive afferent fibers prevails. At the spinal level, neuroplastic sensitizing processes take place that are assumed to underlie the allodynia and hyperalgesia of pain patients. In addition to the lateral spinothalamic tract, the spinoreticular and spinomesencephalic tracts are involved in pain sensations. The medial and lateral thalamus contains several nociceptive nuclei, the medial ones mediating the affective-emotional component of pain, the lateral ones the sensory-discriminative component. In contrast to other sensory modalities, the modality of pain does not have a specific cortical center. The cortical areas that are activated by painful stimuli are distributed over large parts of the cortex surface. During chronic painful conditions, at all levels massive neuroplastic changes take place that lead to rewiring of connections and structural alterations in the nuclei of the nociceptive pathways. In chronic pain patients the neuroanatomy of pain probably differs from that of healthy people.

Effects of a chronic myositis on structural and functional features of spinal astrocytes in the rat.

The study aimed at the question if astrocytes react with morphological or functional changes when a skeletal muscle is pathologically altered. In rats, a myositis was induced in the gastrocnemius-soleus muscle. After 12 days, the immunoreactivity (IR) for glial fibrillary acidic protein (GFAP), morphometric parameters, and fibroblast growth factor-2 (FGF-2) expression of astrocytes were quantitatively evaluated in the dorsal horn of the spinal segment L4. Following inflammation, the area density of GFAP-IR as well as the proportion of astrocytes expressing FGF-2 increased significantly while the degree of astrocyte arborisation decreased as shown by a shape factor. The density of cell nuclei was unchanged suggesting that no myositis-induced cell divisions occurred. The data indicate that spinal astrocytes may influence pain processes particularly by increased FGF-2 synthesis.

[Mechanisms of transition from acute to chronic muscle pain]. / Mechanismen der Chronifizierung von Muskelschmerz.

The present article presents an overview of neurophysiological and neuroanatomical mechanisms that may be involved in the transition from acute to chronic muscle pain. The report is based on data that were obtained in studies on anaesthetised rats in which an acute or chronic myositis was induced experimentally. The inflamed muscle tissue was evaluated using histochemical and immunohistochemical methods, and the impulse activity of single muscle nociceptors or dorsal horn neurones was recorded in electrophysiological experiments in vivo. Chronic myositis was associated with a higher innervation density of the tissue with putative nociceptive free nerve endings that contain the neuropeptide substance P (SP). The nociceptive information from muscle to the spinal cord was largely carried by unmyelinated fibres with tetrodotoxin-resistant Na(+)-channels. At the spinal level, myositis caused changes in the connectivity of dorsal horn neurones which were reflected in an expansion of the input (target) region of the muscle nerve. The central sensitisation can explain the hyperalgesia and spread of pain in patients. Chronic spontaneous muscle pain, however, appears to be due to a lack of NO. The final step in the transition from acute to chronic pain involves structural changes that perpetuate the functional changes. In rat experiments employing nerve lesions or muscle inflammation, such morphological changes become apparent within a few hours after the lesion.

Neurobiological basis for the use of botulinum toxin in pain therapy.

The various serotypes of botulinum toxin (BoNT) exert their action by inhibiting the exocytosis of acetylcholine (ACh) on cholinergic nerve endings. BoNT cleaves proteins (e.g. SNAP-25 or VAMP) that are necessary for the docking of the ACh vesicle to the presynaptic membrane. Without docking, no ACh can be released into the synaptic cleft and the innervated structure is paralyzed. This article focuses on the neuromuscular endplate. The main targets of BoNT therapy are states of muscle hyperactivity such as contractures (in the physiological sense), or spasm and focal dystonias. CONTRACTURES: The "integrated hypothesis" of the formation of myofascial trigger points suggests that a lesion of a muscle damages the endplate so that excessive ACh is released. This causes a local contracture (partial contraction of a muscle fiber) underneath the endplate. The contracture compresses small blood vessels, and the tissue becomes ischemic. Ischemia leads to the release of bradykinin (BKN) and sensitization or excitation of nociceptors. BoNT is a causal therapy in these cases, because it stops the excessive ACh release. SPASM: Reflex spasm in a given muscle can be induced by nociceptive input from neighboring joints or muscles. If the force generated by a spasm is relatively high, it will compress the large blood vessels supplying the muscle. The final effect again is ischemia. In this case a drop in pH may accompany the ischemia and BKN are known to be effective stimulants for muscle nociceptors. DYSTONIA: In cases of weak dystonias, a compression of blood vessels is unlikely. However, the tonic contraction will cause a lowering of pH and a release of ATP. Muscle cells contain ATP at concentrations sufficient to excite muscle nociceptors. In cases of spasm and dystonia, BoNT can abolish the pain by relaxing the muscle. Since many patients report alleviation of their pain before the muscle relaxing effect of BoNT has set in, a direct analgesic action of BoNT is being discussed. Most hypotheses rest on the assumption that BoNT inhibits not only the exocytosis of ACh but also of their neurotransmitters. Such an action could be analgesic if the release of neuropeptides from nociceptive nerve endings is prevented. This way, BoNT could alleviate the pain of neuropathies and various types of headache where neurogenic inflammation plays a role. Another site of an analgesic action could be the postganglionic sympathetic nerve ending that uses norepinephrine and ATP as transmitters. Norepinephrine is known to increase cases of chronic pain, and ATP is a stimulant of muscle nociceptors. If BoNT inhibits the release of these transmitters, it could be analgesic in cases of sympathetically maintained pain including the complex regional pain syndrome.

[Diagnosis and therapy of myofascial trigger points]. / Diagnose und Therapie myofaszialer Triggerpunkte.

AIM: Myofascial trigger points (MTrPs) are hyperirritable tender spots in palpable tense bands of skeletal muscle. Muscle is an orphan organ, no medical specialty claims muscle as its organ. The article aims at filling some of the gaps in the current knowledge of MTrPs. METHODS: The presented findings were partly obtained in experiments on anesthetised rabbits, partly they are the result of ample experience with patients suffering from MTrPs. DIAGNOSIS: Each muscle has a characteristic elicited referred pain pattern that, for active MTrPs, is familiar to the patient. Without a laboratory test or imaging method, diagnosis of MTrPs depends entirely on history and physical examination. MTrP symptoms follow muscle overload, are activated acutely by sudden overload, or develop gradually with prolonged contractions or repetitive activity. The diagnostic skill required depends on considerable innate palpation ability, authoritative training, and extensive clinical experience. THERAPY: Effective treatment methods include manual stretching by trigger-point pressure release, contract-relax, vapo coolant spray-and-stretch, and dry needling or injection of MTrPs. CONCLUSIONS: The integrated hypothesis presents an explanation for the pathophysiology of MTrPs and begins with excessive release of acetylcholine from involved motor endplates. It depends on a new understanding of the abnormality of endplate noise. Biopsies demonstrate segmental shortening of groups of sarcomeres in individual muscle fibres and possibly waves of contracted sarcomeres to account for palpable taut bands.

[Assessment of muscle pain and hyperalgesia. Experimental and clinical findings]. / Messung von Muskelschmerz und Hyperalgesie. Experimentelle und klinische Befunde.

AIM: It is evident that muscle hyperalgesia and referred pain have an important role in chronic musculoskeletal pain. More knowledge of the basic mechanisms involved and better methods of assessing muscle pain in clinical practice are needed so that treatment regimens can be revised and improved. METHODS: Methods of quantitative sensory testing of muscle pain and associated phenomena are described. These methods make it possible to evaluate manifestations of muscle pain in a standardised way both in patients suffering from musculoskeletal pain and in healthy volunteers. RESULTS: Elevated muscle sensitivity becomes manifest as (1) pain evoked by a normally non-noxious stimulus (allodynia), (2) abnormally intense pain evoked by noxious stimuli (hyperalgesia), or (3) unusually large areas of referred pain with associated somatosensory changes. These changes can occur as increased somatosensory sensitivity of deep somatic tissues or of the skin in areas of pain referral. Some manifestations of sensitisation in chronic musculoskeletal pain patients, such as expansion of the areas of referred muscle pain, can be explained by the extra segmental spread of central sensitisation seen in animal experiments. CONCLUSIONS: An important part of the manifestations of pain in chronic musculoskeletal disorders may be due to peripheral and central sensitisation processes, which are also involved in the transition from acute to chronic pain. Knowledge of these processes has expanded enormously in recent years; it should be utilised when new intervention strategies are designed.

[What is different about muscle pain?]. / Was ist das Besondere am Muskelschmerz?

BACKGROUND: The bulk of available knowledge about pain mechanisms is derived from studies on cutaneous pain. However, deep somatic pain (from muscle, fascia, tendon, joint) is clinically of much greater importance. The existing subjective differences between muscle and skin pain (e.g. muscle pain is poorly localized and shows referral) suggest that muscle and skin pain do not share the same mechanisms. AIMS OF THE STUDY: To answer the question if the nociceptive information from muscle has neuroanatomical connections and mechanisms that are distinct from those of cutaneous nociception. MATERIALS AND METHODS: The results were obtained partly in animal experiments on anaesthetised rats, partly in studies with healthy subjects or fibromyalgia patients. RESULTS: 1. At the spinal level, the excitatory effects of unmyelinated afferent fibres from muscle are subject to a strong segmental inhibition by myelinated afferent fibres, which is largely absent in the effects of cutaneous C fibres. 2. At the cortical level, experimental muscle pain excites other regions than does cutaneous pain. 3. At the level of descending pain-modulating pathways, interruption of the activity in these pathways leads to higher activity of nociceptive neurones caudal to the site of interruption. The activity was higher in neurones with input from deep nociceptors than in cells mediating cutaneous nociception. CONCLUSIONS: The data demonstrate that at all central nervous levels the connections and processing of nociceptive information from muscle and skin are different. The findings regarding descending pain-modulating pathways suggest that a dysfunction of this system could lead to chronic deep pain as in fibromyalgia.

Lesions of rat skeletal muscle after local block of acetylcholinesterase and neuromuscular stimulation.

In skeletal muscle, a local increase of acetylcholine (ACh) in a few end plates has been hypothesized to cause the formation of contraction knots that can be found in myofascial trigger points. To test this hypothesis in rats, small amounts of an acetylcholinesterase inhibitor [diisopropylfluorophosphate (DFP)] were injected into the proximal half of the gastrocnemius muscle, and the muscle nerve was electrically stimulated for 30-60 min for induction of muscle twitches. The distal half of the muscle, which performed the same contractions, served as a control to assess the effects of the twitches without DFP. Sections of the muscle were evaluated for morphological changes in relation to the location of blocked end plates. Compared with the distal half of the muscle, the DFP-injected proximal half exhibited significantly higher numbers of abnormally contracted fibers (local contractures), torn fibers, and longitudinal stripes. DFP-injected animals in which the muscle nerve was not stimulated and that were allowed to survive for 24 h exhibited the same lesions but in smaller numbers. The data indicate that an increased concentration of ACh in a few end plates causes damage to muscle fibers. The results support the assumption that a dysfunctional end plate exhibiting increased release of ACh may be the starting point for regional abnormal contractions, which are thought to be essential for the formation of myofascial trigger points.