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S Mense

Publications and source records attributed to S Mense.

At least 19 recordsLinked to original sources
PubMed2006

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.

Animals↗
PubMed2004

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.

Afferent Pathways↗
PubMed2004

[Mechanisms of transition from acute to chronic muscle pain].

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.

Acute Disease↗
PubMed2004

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.

Analgesia↗
PubMed2004

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.

Brain↗
PubMed2003

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.

Acetylcholine↗
PubMed2003

[Diagnosis and therapy of myofascial trigger points].

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.

Animals↗
PubMed2003

[Assessment of muscle pain and hyperalgesia. Experimental and clinical findings].

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.

Humans↗
PubMed2003

[What is different about muscle pain?].

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.

Humans↗
PubMed2002

Thermosensitivity of muscle: high-intensity thermal stimulation of muscle tissue induces muscle pain in humans.

Small-calibre afferent units responding to thermal stimuli have previously been reported to exist in muscle. The question as to whether these receptors in humans mediate subjective thermal sensations from muscle remains unresolved. The aims of the present study were to determine in humans whether intramuscular injection of warm and cold isotonic saline elicits temperature sensations, muscle pain or any other sensations. In 15 subjects, no thermal sensations assessed on a temperature visual analogue scale (VAS) could be detected with intramuscular injections of isotonic saline (1.5 ml) into the anterior tibial muscle at temperatures ranging from 8 to 48 degrees C. The same subjects recorded strongly increasing scores on a temperature VAS when thermal stimuli in the same intensity range were applied to the skin overlying the muscle by a contact thermode. However, I.M. isotonic saline of 48 degrees C induced muscle pain with peak scores of 3.2 +/- 0.8 cm on a VAS scale ranging from 0 to 10 cm. Using the the McGill pain questionnaire a subgroup, of subjects qualitatively described the pain using the 'thermal hot' and 'dullness' word groups. Temperature measurements within the muscle during the stimulating injections showed that the time course of the pain sensation elicited by saline at 48 degrees C paralleled that of the intramuscular temperature and far outlasted the injection time. The present data show that high-intensity thermal stimulation of muscle is associated with muscle pain. High-threshold warm-sensitive receptors may mediate the pain following activation by temperatures of 48 degrees C or more. Taken together, the data indicate that thermosensation from a given volume of muscle is less potent than nociception.

Adult↗
PubMed2001

[Pathophysiology of low back pain and the transition to the chronic state - experimental data and new concepts].

The present article concentrates on mechanisms that lead to the excitation of nociceptors in soft tissues and nociceptive neurones in the spinal dorsal horn. These mechanisms may contribute to the so-called unspecific low back pain. Properties of nociceptors in soft tissues: A nociceptive ending in soft tissue contains a multitude of receptor molecules in its membrane. The molecular receptors include binding sites for algesic substances that are released during painful stimulation or pathologic alterations of the tissue: bradykinin (BK), serotonin (5-HT), prostaglandin E2 (PG E2), adenosine triphosphate (ATP) and protons (H(+)). The excitation and sensitisation of nociceptors by these substances can be explained by the binding of the substances to the receptor molecules in the membrane of the receptive ending and ensuing opening of ion channels or activation of metabolic cascades. Purinergic receptor molecules in the membrane of nociceptors are activated by ATP. These receptors may be of particular importance for deep somatic pain, because ATP is present in large amounts in muscle tissue and is released during muscle damage. ATP-sensitive nociceptors appear to be distinct from nociceptors that can be excited by protons. The conduction of nociceptive information from muscle to the spinal cord is partly carried by unmyelinated fibres that possess tetrodotoxin-resistant (TTX-r) Na(+)-channels. Therefore, a drug that specifically blocks TTX-r Na(+)-channels would be a new attractive tool in the treatment of patients with deep somatic pain. Chronic muscle lesions such as a myositis have been shown to be associated with a higher innervation density of the tissue with free nerve endings that contain the neuropeptide substance P (SP). Many of these endings are likely to be nociceptors. Since a painful stimulus that acts on a muscle with increased nociceptor density will excite more nociceptors and elicit more pain, the increase in nociceptor density constitutes a peripheral mechanism for hyperalgesia. In muscle free nerve endings - many of which are nociceptive - the neuropeptides SP, calcitonin gene-related peptide (CGRP) and somatostatin have been shown to be present. These substances are released from the receptive endings in muscle when they are stimulated. SP and CGRP have a strong effect on blood vessels and induce local vasodilatation and oedema. The local oedema in the vicinity of the nociceptor is associated with the release of BK from plasma proteins, which increases the excitability of the nerve ending (see below). Thus, a local vicious cycle forms that may contribute to the formation of trigger points. Sensitisation of nociceptors and peripheral hyperalgesia: Nociceptors are easily sensitised, i.e. following a conditioning stimulus they are more sensitive to the unconditioned stimulus. In animals and humans, the responses to injections of BK can be increased by 5-HT or PG E2. The responses of muscle nociceptors to mechanical stimuli are likewise enhanced after administration of BK. During overuse, ischemia or inflammation of soft tissues, the tissue concentrations of BK, PG E2, and 5-HT are elevated and sensitise muscle nociceptors. A sensitised nociceptor is excited and elicits pain when innocuous mechanical stimuli act on the muscle, e.g. during contractions or stretch. Therefore, in chronically altered soft tissues, weak everyday stimuli are likely to cause pain. Mechanisms at the spinal level: In experiments on rats in which a myositis of the gastrocnemius-soleus (GS) muscle was induced experimentally, the effects of a peripheral painful lesion on the discharge behaviour of sensory dorsal horn neurones were studied. One of the main effects of the myositis was an expansion of the input (target) region of the muscle nerve, i.e. the population of dorsal horn neurones responding to an electrical standard stimulus applied to the GS muscle nerve grew larger. One reason for the myositis-induced expansion of the input region is hyperexcitability of the neurones caused by the release of SP and glutamate from the spinal terminals of muscle afferents with ensuing activation of NMDA channels in dorsal horn neurones (central sensitisation). The central sensitisation is of clinical importance because it can explain the hyperalgesia and spread of pain in patients. In contrast to excitability, the resting activity of dorsal horn neurones - which is likely to induce spontaneous pain in patients - does not appear to depend on the release of SP and glutamate but on the concentration of nitric oxide (NO) in the spinal cord. A pharmacological block of the NO synthesis led to a significant increase in background activity without affecting the excitability of the dorsal horn neurones. Such an increase in background activity was observed exclusively in nociceptive neurones, i.e. a local lack of NO in the spinal cord induces spontaneous pain. According to data from animal experiments, a decrease in the spinal NO concentration occurs as a sequel of a chronic muscle lesion; therefore, a lack of NO is a probable factor for the induction of chronic spontaneous pain. Normally, lesion-induced pain subsides and does not develop into chronic pain. The mechanisms governing the return to normal neuronal behaviour after a peripheral lesion are not well studied. Probably, the activation of inhibitory mechanisms, e.g. increased spinal synthesis of GABA or elevated activity of the descending antinociceptive system contribute to the restoration of normal function. The final step in the transition from acute to chronic pain are structural changes that perpetuate the functional changes. In the rat myositis model, an increase in the number of synapses on the surface of NO-snythesizing cells was present 8 h following induction of the myositis. These data show that structural changes appear quite early in the development of a painful disorder. A novel hypothesis for the development of chronic pain states that a strong nociceptive input to the spinal cord leads to cell death predominantly in inhibitory interneurones. Most of these interneurones are assumed to be tonically active; when their number decreases, the nociceptive neurones are chronically disinhibited and elicit continuous pain also in the absence of a noxious stimulus.

Animals↗
PubMed2001

[Anatomical background of low back pain: variability and degeneration of the lumbar spinal canal and intervertebral disc].

The central and lateral lumbar canals constitute complex osteofibrous neurovascular tunnels, allowing movement and deformation of the spine without loss of their main configuration. Intervertebral discs play an important role in determining their configuration. Disc degeneration may alter or even threat the functional anatomical relationships between successive adjacent "juncturae" of the vertebral column. Shape and morphometric aspects of the bony neural canals reveal level dependency [39], inter-individual variation [11], and are particularly susceptible for changes with aging [49]. Articular tropism and other left-right differences may influence their morphology. In the epidural compartments behind the vertebral bodies, a sagittal membrane may totally or partly connect the deeper layer of the posterior longitudinal ligament (PLL) with the posterior midline of the vertebral body. This membrane is considered clinically significant in the prevention of movement of disc material from one side to the other at the level of the vertebral bodies [44]. Meningovertebral ligaments represent a heterogenous group of membranous formations, connecting the dura with the PPL and other elements of the spinal canal. They prevent the dura from moving away from the bony container. These ligaments may vary from loose areolar tissue to clearly individualised ligaments and from pure midsagittal septa to more laterally oriented attachments. A double cross vault structure between the PPL and the dura mater often extends from L3 to the end of the dural envelope [3]. A retrospective study of medial and paramedial attachments in CT- and MRT-scans confirmed the presence of a mediosagittal structure below L3 in 35% of the cases 7). It was hypothesized that meningovertebral ligaments may play a [7] role as a barrier to transverse displacement of extruded disc material [43]. The surrounding morphology renders the lateral neural canal its typical inverted teardrop shape [39]. The subpedicular notch of the upper vertebra provides the widest part and represents the neural foramen strictu sensu. The posterolateral aspect of two articulating vertebrae and the interposed intervertebral disc constitute the anterior wall. The morphology of the anteroinferior aspect of the intervertebral foramen strongly depends on the condition of the apophyseal rings and the intervertebral disc. The latter may show a slight physiological posterior bulging at lower lumbar levels. The posterior wall of the nerve root canal is represented by the ligamentum flavum, the pars interarticularis of the upper vertebra, and the superior articular facet of the vertebra below. Thickening of the ligamentum flavum must be considered in relationship to alterations of anterior components: trabecular reorganization and spreading of vertebrae in aging [49], and disc degeneration [38, 49]. Nerve root sleeves display a level dependent, variable oblique course from their emanation from the thecal sac towards the outer third of the neural canal [39]. The presence of anamalous lumbosacral nerve roots may result in considerable course alterations, originating from an abnormal high or low level emanation, conjoined nerve roots, a double set of nerve roots or anastomosis between nerve roots of adjacent levels [20]. Variation exists in the position of the dorsal root ganglia (DRG) relative to the intervertebral foramen. An intraforaminal position seems to be more common at L4 and L5 levels; an intraspinal position has to be expected for the S1 DRG. Intraspinal position of L4 and L5 DRG renders them more susceptible to compression from a superior articular facet or a bulging disc. Cases of extraforaminal positions of dorsal root ganglia have been reported at L4 and L5 levels [22]. On its recurrent course through the lateral canal, the sinuvertebral nerve(s) supplies the laterodorsal outer annulus of the intervertebral disc, the PLL, the anterior 2/3 of the dural sac and the anterior vascular plexus [4, 14]. Many blood vessels pass through the lateral neural canal: the anterior and posterior spinal canal branches, anterior and posterior radicular branches, and veins of the anterior and posterior internal vertebral venous plexus [9]. Per segment, one ore two thick and one to four thin sinuvertebral nerves (SVN) originate from rami communicantes close to the connection of the latter to the spinal nerve [14]. The extensive ramifications of the thin SVNs complete a thorough network at the floor of the central lumbar canal. A large part of it supplies the PLL. The PLL is assumed to play an important role in proprio- and nociception [34, 39]. It is probably one of the first structures to mediate nociceptive information from disc tissue [14]. After injection of neuronal tracers into the sympathetic trunk at L3-L4 in rats, labeled cells were found in higher DRGs as well as labeled nerve fibers in the dura mater at lower levels. These findings indicate both a segmental and a non segmental pathway of sensory innervation of the dura mater and a role of higher DRGs in mediating LBP [25]. In the neighborhood of the SVN, other small branches emanate from the rami communicantes and join the dorsal ramus and the segmental artery that enters the neural canal. The sympathetic nerve plexus inside the anterior longitudinal ligament and the SNVs provide a network of nerve fibers around the vertebral bodies and intervertebral discs. These pathways explain the sympathetic component of the innervation of a number of spinal structures. The dorsal ramus innervates the facet joints at the corresponding level and one below, before it gives off muscular and cutaneous branches.

Aging↗
PubMed2001

[A lack of NO in the spinal cord as a possible factor for the occurrence of spontaneous pain].

AIM OF THE STUDY: The role of nitric oxide (NO) in the processing of nociceptive information is controversely discussed. The present review aims at answering the questions how a spinal lack of NO influences the discharge behaviour of dorsal horn neurones, and if the NO-synthesising neurones exhibit a change in histologically visualised cell numbers under the influence of a nociceptive input from the body periphery. METHODS: The data were obtained from anaesthetised rats. The impulse activity of single sensory dorsal horn neurones was recorded with glass microelectrodes. In the spinal segments studied, the NO synthase (NOS) was blocked with L-NAME. The NO-synthesising cells were visualized histochemically with the diaphorase reaction or immunohistochemically with antibodies to the NOS. RESULTS: The inhibition of the NO synthesis by L-NAME was followed by a marked increase in the background activity almost exclusively in nociceptive neurones. In the histological evaluation, the NO-synthesising neurones reacted to a nociceptive input with an initial increase in cell number which was followed by a decrease. CONCLUSIONS: Normally, a tonic release of NO in the spinal cord appears to exist which inhibits the discharges of nociceptive dorsal horn neurones. Accordingly, a local lack of NO synthesis leads to an increase in the electrical activity in these neurones. Under chronic painful conditions there is a decrease in the number of NO-synthesising cells which is associated with a lack of NO in the dorsal horn. If such changes occur also in patients they are likely to cause spontaneous pain. Thus, NO could be an important factor for spontaneous pain in patients with chronic painful lesions in the body periphery.

Animals↗
PubMed2001

Tetrodotoxin-resistant conductivity and spinal effects of cutaneous C-fibre afferents in the rat.

The effect of the sodium channel blocking agent tetrodotoxin (TTX) on signal processing in afferent fibres of dorsal roots was tested in Sprague-Dawley rats. TTX applied to the dorsal roots L4-L6 blocked the fast afferent volleys from the sural nerve, which was stimulated electrically with supramaximal strength for A-fibres. Afferent C-fibre compound action potentials (CAPs) elicited by electrical stimulation of the dorsal root L5 peripherally from the TTX block or by electrical stimulation of the sural nerve likewise disappeared from the recording. Cord dorsum potentials (CDPs) recorded at the dorsal root entry zone of L4 were blocked completely if elicited by A-fibre volleys. In contrast, CDPs elicited by C-fibre stimulation persisted with longer latency and reduced amplitude in the first part of the CDP. During TTX block, C-fibre potentials could also be recorded from dorsal root filaments after stimulation of the sural nerve or the dorsal root L5 peripherally of the TTX-block. The results suggest that in the axonal membrane of cutaneous C-afferents, both TTX sensitive and TTX-resistant voltage gated sodium channels exist, the latter being responsible for the propagation of signals in a portion of C-fibres after TTX application. The TTX-resistant portion of the afferent potential does not seem to contribute much to the afferent C-fibre CAP before TTX application, but its central effects seem to be overproportionally strong.

Action Potentials↗
PubMed2001

Fibroblast growth factor-2 acutely influences the impulse activity of rat dorsal horn neurones.

The neurotrophic and neuroprotective actions of fibroblast growth factor-2 (FGF-2) are well-established. The signal cascade mediating these effects includes steps that are likely to influence also the electrical properties of neurones. However, the possibility that FGF-2 may acutely affect the processing of neuronal impulse activity is largely unexplored. In the present study the impulse activity of single dorsal horn neurones was recorded in the rat during ionophoretical administration of FGF-2 close to the neurones. Before and during FGF-2 ionophoresis the receptive field of each cell was tested with defined mechanical stimuli. At a concentration of 10 nM in the ionophoresis pipette, FGF-2 reduced the responses of the cells to mechanical stimulation. There was no preferential action of FGF-2 on a particular functional type of dorsal horn neurone; both non-nociceptive and nociceptive cells exhibited a reduced mechanical responsiveness. The background (ongoing) activity was also depressed in most neurones. The results of the study show that in addition to neurotrophic and neuroprotective actions FGF-2 has an acute inhibitory influence on the impulse activity of spinal sensory neurones. This depression of neuronal activity could add to the neuroprotective action of FGF-2 by counteracting glutamate excitotoxicity following a central nervous trauma.

Action Potentials↗
PubMed2001

The peripheral apparatus of muscle pain: evidence from animal and human studies.

The peripheral apparatus of muscle pain consists of nociceptors that can be excited by endogenous substances and mechanical stimuli. Histologically, the nociceptors are free nerve endings supplied by group III (thin myelinated) and group IV (nonmyelinated) afferents with conduction velocities less than 30 m/s. At the molecular level, nociceptors have receptors for algesic substances, such as bradykinin, serotonin, and prostagladin E2. The purinergic receptors and tetrodotoxin-resistant sodium channels might be new important targets for the treatment of muscle pain. Algesic substances (capsaicin, bradykinin, serotonin, potassium chloride, and hypertonic saline) and other stimuli (ischemia, strong mechanical stimuli, and electrical stimuli) have been shown to induce nociception from muscle in animals and muscle pain in humans. Muscle nociceptors can be sensitized to chemical and mechanical stimuli. Contrary to a former belief, the sensitization is not an unspecific process; rather, it is caused by endogenous algesic substances binding to highly specific receptor molecules in the membrane of the nociceptive ending. For example, animal studies showed that serotonin sensitizes muscle nociceptors to chemical and mechanical stimuli. Later, human studies showed that serotonin combined with bradykinin induces muscle hyperalgesia to pressure. The sensitization process by endogenous substances that are likely to be released during trauma or inflammatory injury is probably the best established peripheral mechanism for muscle tenderness and hyperalgesia.

Animals↗
PubMed2000

A block of spinal nitric oxide synthesis leads to increased background activity predominantly in nociceptive dorsal horn neurones in the rat.

Previous studies have shown that nitric oxide (NO) has a strong influence on the background (resting) activity of dorsal horn neurones. The background activity of dorsal horn neurones is generally assumed to be responsible for the presence of paraesthesia or spontaneous pain in patients depending on the functional type of neurones that are active. However, nothing is known about a possible selective action of NO - or a lack of NO - on a particular functional class of neurone. In the present study the background activity of lumbar dorsal horn neurones was examined in anaesthetized rats before and during spinal superfusion with L-NAME, an unspecific blocker of NO synthesis. The neurones were divided into five classes: (1) low-threshold mechanosensitive (LTM) cells with deep receptive fields (LTM deep units); (2) LTM cells with cutaneous receptive fields (LTM cutaneous units) (these two classes were considered to be non-nociceptive); (3) high-threshold mechanosensitive (HTM) deep cells; (4) HTM cutaneous cells; and (5) multireceptive (MR) cutaneous cells (the last three classes were assumed to be nociceptive). HTM neurones increased the frequency of their background activity significantly during L-NAME superfusion and 80% of the initially silent neurones became active after administration of the NOS blocker. MR neurones likewise increased their background activity. In contrast, the background activity of non-nociceptive (LTM) neurones was not significantly affected. The results support previous studies showing that NO has a tonic depressing effect on the background activity of dorsal horn neurones and demonstrate for the first time that this effect is largely restricted to nociceptive neurones. Therefore, a reduction in spinal NO synthesis which often occurs during a long-lasting peripheral lesion is likely to cause increased background activity in nociceptive neurones and thus might contribute to spontaneous pain in patients.

Animals↗