The possible role of substance P in eliciting and modulating deep somatic pain.
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Afferent Pathways↗
Biomedical subjects
S Mense
Publications and source records attributed to S Mense.
Fibroblast growth factor-2 depresses the impulse activity of rat dorsal horn neurones in vivo.
The neurotrophic and neuroprotective actions of fibroblast growth factor-2 (FGF-2) are well known. Almost no information is available, however, about possible FGF-2 effects on neuronal electrical activity in vivo. In the present study, the effects of spinal application of FGF-2 on the discharges of lumbar dorsal horn neurones were studied in anaesthetized rats. FGF-2 depressed the background activity and reduced the proportion of cells dominated by low-threshold mechanosensitive input. In contrast, the proportion of units with C-fibre input was increased. Nitric oxide appears not to be involved in the depression of background activity. The results suggest that elevated levels of intrathecal FGF-2 affect sensory processing by depressing low-threshold mechanoreception.
Animals↗
Blockade of nitric oxide synthase differentially influences background activity and electrical excitability in rat dorsal horn neurones.
A previous study has shown that inflammation of the gastrocnemius-soleus muscle in rats leads to an increase in excitability of dorsal horn neurones particularly in the spinal segment L3. Here, we have blocked the nitric oxide synthase (NOS) in L3 by spinal cord superfusion with NG-monomethyl-L-arginine (L-NMMA) to find out if this effect is due to a release of nitric oxide (NO). L-NMMA had no influence on the excitability of L3 neurones but caused a marked increase in background activity. The L-NMMA effect on background activity was also present in rats with intact muscle. The data show that the myositis-induced increase in spinal excitability is not mediated by NO. The background activity, however, appears to be strongly dependent on NO production.
Amino Acid Oxidoreductases↗
Changes in NADPH-diaphorase activity in the rat dorsal horn following an acute experimental myositis.
Previous neurophysiological experiments have shown that in rats with an acute myositis of the gastrocnemius-soleus muscle, dorsal horn neurones exhibit an increase in responsiveness to peripheral stimulation and in background activity. The present study investigated the possible correlation between changes in NADPH-diaphorase activity and neurophysiological alterations. In the animals used for the electrophysiological experiments the diaphorase activity in sections of the lumbar spinal cord was determined with the NADPH-nitroblue tetrazolium reaction. The main findings was a massive reduction in the number of diaphorase-positive cells in the superficial dorsal horn in animals with a myositis. The staining intensity in the remaining neurones was unchanged. The results are interpreted as indicating that the myositis in addition to the surgical operations represents a supramaximal input to the dorsal horn causing neurotoxic effects in diaphorase- positive neurones.
Acute Disease↗
Effects of an acute muscle nerve section on the excitability of dorsal horn neurones in the rat.
A previous study of this laboratory showed that an acute myositis (which is associated with increased activity in slowly conducting muscle afferent fibres) is followed by marked excitability changes in the dorsal horn within a few hours. The present work addresses the question as to how the responsiveness of dorsal horn neurones changes when the same muscle nerve is transected. In anaesthetized rats, an axotomy of the gastrocnemius-soleus (GS) muscle nerves was performed and the electrical and mechanical excitability of single dorsal horn neurones in the lumbar spinal cord determined 2-8 h after the lesion. Axotomy led to a decrease in the proportion of neurones responding to A-fibre input from the cut nerve and to an increase in the efficacy of sural and peroneal nerve stimulation. The change in GS input became significant only 5-8 h after the lesion and could reflect the beginning of neuroplastic changes. The change in sural and peroneal input was most marked 2-5 h after axotomy and is probably due to fast neuronal processes. The efficacy of C-fibre input from the sural and peroneal nerves increased significantly in the lateral dorsal horn only. In comparison with the effects of an acute myositis, the axotomy had opposite effects with regard to the GS input, but similar effects with regard to the C-fibre drive from the other nerves. It is concluded that transection of a muscle nerve is similarly effective in inducing acute changes in dorsal horn excitability as is an increase in muscle nerve activity.
Animals↗
Leukotriene D4 depresses the mechanosensitivity of group III and IV muscle receptors in the rat.
In anaesthetized rats the influence of leukotriene (LT) D4 on the discharges of group III and IV muscle receptors was studied. The impulse activity of single slowly conducting afferent fibres from the gastrocnemius-soleus muscle was recorded and their responsiveness to mechanical stimulation of the muscle determined. Intramuscular injections of LTD4 100 ng or 1 microgram were made into the receptive field of units in intact and carrageenan-inflamed muscle in order to find out whether LTD4 has a sensitizing action on the receptors. The LT reduced the mechanically induced responses in intact but not in inflamed muscle, whereas the background activity was not influenced in intact muscle and showed a decrease in inflamed muscle. The results demonstrate that LTD4 does not belong to the substances which sensitize nociceptors and cause subjective tenderness following a tissue lesion.
Afferent Pathways↗
Calcitonin gene-related peptide-immunoreactivity in functionally identified primary afferent neurones in the rat.
In anaesthetized rats, intracellular recordings were made from the somata of lumbar (L4 and L5) dorsal root ganglion cells. The impaled afferent units were first functionally classified by testing the peripheral receptive endings with mechanical stimuli and then iontophoretically injected with a fluorescent dye. Serial sections of the dorsal root ganglion containing the injected soma were incubated with an antibody solution against calcitonin gene-related peptide (CGRP). Somata displaying calcitonin gene-related peptide-immunoreactivity (CGRP-IR) possessed receptive endings in the skin and deep somatic tissues (muscle, fascia, tendon, joint). The majority of calcitonin gene-related peptide-immunoreactive (CGRP-ir) neurones had conduction velocities below 2.5 m/s; only a few neurones conducted faster than 10 m/s. The immunostained somata were small to medium-sized (cross-sectional area < 1200 microns 2). With one exception, CGRP-IR was found in all types of ending studied, but the proportion of CGRP-ir neurones differed. Immunostained somata were rare among cutaneous and deep low-threshold mechanosensitive units (e.g. hair follicle and muscle spindle units). CGRP-ir somata were most frequent among high-threshold mechanosensitive (presumably nociceptive) afferent neurones (four out of six cells). The data suggest that CGRP can be expressed not only in nociceptive but also in many other types of primary afferent neurone, the condition being that the conduction velocity is slow and/or the cell soma small.
Animals↗
Functional reorganization in the rat dorsal horn during an experimental myositis.
In anaesthetized rats, the influence of an acute inflammation (2-8 h duration) of the gastrocnemius-soleus (GS) muscle on the excitability of dorsal horn neurones was studied using a mapping procedure. One of the main effects of the myositis was that the neurone population responding to GS A-fibre input increased in size. The increase was most marked in the lateral segments L6-L3 which received little input from the GS muscle in control animals. Excitability testing showed a myositis-induced lowering in threshold, combined with an increase in latency, jitter and input convergence. This suggests that new oligo- or polysynaptic connections become functional under the influence of a myositis. Neuronal effects induced by C fibres in the GS nerves were not significantly altered by a myositis, but C fibre-induced activations from the peroneal and sural nerves increased in the lateral dorsal horn. The results show that an acute myositis leads to marked changes in the functional connectivity of the dorsal horn within a few hours. The main increase in excitability took place in the lateral dorsal horn, where many neurones acquired a new input from the GS muscle. This mechanism may be involved in the spread or referral of muscle pain.
Animals↗
Appearance of new receptive fields in rat dorsal horn neurons following noxious stimulation of skeletal muscle: a model for referral of muscle pain?
To test the hypothesis that painful stimuli to skeletal muscle lead to a widespread unmasking of synaptic connections in dorsal horn neurons, intramuscular injections of bradykinin (BKN) were made outside the receptive fields (RFs) of these cells in the rat. Following BKN injections, new RFs all of which were located in the deep tissues and had high mechanical thresholds appeared in 9 out of 21 (42.8%) nociceptive dorsal horn neurons which originally had a single RF in deep tissues or in the skin. The appearance of new RFs may lead to a mislocation of the source of pain if in fact the impulse activity of a nociceptive dorsal horn neuron contains information on the site of the stimulus.
Animals↗
The influence of mechanical stimuli and of acetylsalicylic acid on the discharges of slowly conducting afferent units from normal and inflamed muscle in the rat.
In anaesthetized rats, the influence of an experimental inflammation and of acetylsalicylic acid (ASA) on the discharge properties of muscle receptors with slowly conducting afferent fibres was studied using a single-fibre recording technique. Following the induction of a myositis with carrageenan, the proportion of units having background activity and the frequency of the background discharge were significantly increased. The latter change was particularly prominent in high-threshold mechanosensitive (HTM) units. There was evidence for an inflammation-induced lowering of mechanical threshold in HTM units, but the change was not statistically significant. Administration of ASA intravenously led to a decrease in the frequency of background discharge in some units while others were unaffected, although they appeared to be sensitized by the inflammation. If one assumes that at least some of the HTM receptors fulfil nociceptive functions, the results suggest that the pain and tenderness of an inflamed muscle is largely due to a sensitization and hence increased activity of nociceptive muscle receptors. The sensitization is only partially abolished by ASA.
Action Potentials↗
Nociception from skeletal muscle in relation to clinical muscle pain.
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Animals↗
Effects of a novel piperazine derivative (CGP 29030A) on nociceptive dorsal horn neurons in the rat.
In anaesthetized rats and cats, the effects of the piperazine derivative CGP 29030A on the discharges of functionally identified dorsal horn neurons and gamma-motoneurons was studied. The compound exhibited a marked inhibitory action on presumably nociceptive dorsal horn neurons that processed input from high-threshold mechanosensitive receptors in the skin and deep somatic tissues (muscle, tendon, joint). Significant effects were obtained at a dose of 10 mg/kg p.o. and higher; the onset of action was fast (approximately 10 min). In contrast to presumably nociceptive dorsal horn neurons, cells having input from low-threshold mechanosensitive receptors in the skin and deep tissues were not affected by the compound. Thus CGP 29030A has a quite specific action on dorsal horn neurons that probably mediate pain. Systemic effects on the blood pressure and on the activity of sympathetic efferent fibres did not occur. The lack of effect of CGP 29030A on nociceptive neurons in spinalized animals suggests that the site of action is not the segmental spinal cord but the supraspinal CNS. gamma-motoneurons supplying the gastrocnemius-soleus muscle were likewise inhibited by the compound but at a higher dose (equal to and exceeding 30 mg/kg). The data show that CGP 29030A is a compound with marked and specific analgesic action. As it also inhibits gamma-motoneurons, CGP 29030A may be of benefit in the treatment of painful disorders which are complicated by increased motor activity (cramp, spasm).
Action Potentials↗
Discharge behaviour of feline gamma-motoneurones following induction of an artificial myositis.
The study was undertaken to test the widely held hypothesis that a painful lesion of the skeleto-motor system leads to an increase in the neuromuscular component of muscle tone by activating gamma-motoneurones in the affected region. In chloralose-anaesthetized cats, artificial myositis was induced in the lateral gastrocnemius-soleus (LGS) muscle and several hours later the impulse activity was recorded from single gamma-motoaxons supplying the medial gastrocnemius (MG) muscle. Under the conditions of the study, the majority of the fusimotor neurones had a resting activity and could be readily excited by natural stimuli. In contrast to the assumptions of the working hypothesis, the gamma-motoneurones in the myositis animals were not activated but showed a strong inhibition; both resting activity and excitability by electrical and natural stimuli were decreased. Additional recordings from fusimotor neurones of a flexor muscle (tibialis anterior, TA) demonstrated that in the preparation used, the behaviour of the flexor gamma-motoneurones was different from extensor ones in that the former usually had no resting activity and did not respond to natural stimuli. The only discernible effect of a myositis of the LGS muscle on the TA gamma-motoneurones was a decrease in their electrical reflex threshold. The results of the study do not support the assumption that a painful muscle lesion is followed by an activation of the gamma-loop that leads to an increase in muscle tone. Instead, the data may offer an explanation for the weakness and--in chronic cases--the reflex atrophy of lesioned muscles.
Acoustic Stimulation↗
The effects of intracerebroventricular injection of naloxone, phentolamine and methysergide on the transmission of nociceptive signals in rat dorsal horn neurons with convergent cutaneous-deep input.
In anaesthetized rats, recordings were made from nociceptive dorsal horn neurons with convergent input from the skin and deep somatic tissues. The results of a previous study have shown that in these neurons the input from deep nociceptors is subjected to a much stronger tonic descending inhibition than is the input from cutaneous nociceptors. The aim of the present study was to find out whether at supraspinal levels opioidergic, adrenergic, or serotoninergic transmitters are involved in this quite specific inhibition of deep nociception. Injections of naloxone, phentolamine, and methysergide into the third ventricle showed that only naloxone is capable of abolishing the tonic inhibition of the deep nociceptive input to spinal neurons. The input from cutaneous nociceptors to the same cells was largely unaffected by naloxone. Thus the effects of intracerebroventricular injection of naloxone resembled those obtained with a spinal cold block in a previous study; with the exception that the increase in background activity--which is prominent during cold block--was missing after the injection of naloxone. The present results demonstrate that the tonic descending inhibition of the deep nociception operates with opioidergic synapses at the supraspinal level. In contrast, supraspinal adrenergic and serotoninergic mechanisms do not appear to contribute to the tonic inhibition. The data confirm and extend previous results which suggested that a particular portion of the descending antinociceptive system may act mainly on the input from deep nociceptors. Pharmacologically, this particular portion seems to be opioidergic in nature.
Animals↗
Considerations concerning the neurobiological basis of muscle pain.
Nociceptors in skeletal muscle can be sensitized by substances that are released from pathologically altered tissue. In the sensitized state, nociceptors can be activated by low-intensity stimulation; this is probably one of the mechanisms producing deep tenderness. Dorsal horn cells processing input from muscle nociceptors often have multiple receptive fields and additional input from other deep tissues or skin. This may be one of the reasons for the diffuse and ill-localized nature of muscle pain. The degree of convergence from deep tissues and skin in neurones with muscle input can be increased by noxious stimulation of deep tissues. This mechanism might explain phenomena such as spread and referral of muscle pain. In the development of chronic muscle pain, vicious circles may be involved which operate locally in the damaged tissue or via spinal reflexes that alter the biochemical environment of the nociceptors in skeletal muscle.
Animals↗
[Electrophysiology of muscular nociception in ischemia and oxygen deficiency].
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Animals↗
Somatotopical arrangement of rat spinal dorsal horn cells processing input from deep tissues.
Extracellular recordings were made from 29 dorsal horn neurones which could be driven by mechanical stimulation of deep tissues, in spinal segment L4 of rats. The recording sites were marked by iontophoresis of pontamine sky blue. According to the location of the receptive fields the cells were classified as deep neurones (12 cells), which had input from deep tissues only, and as cutaneo-deep neurones (17 cells), which had receptive fields in both skin and deep tissues. The deep cells showed a correlation between the recording sites in the dorsal horn and the location of the receptive fields on the hind-limb: the more distal a deep receptive field was situated on the hind-limb the more medial was the location of the recording site in the dorsal horn. In cutaneo-deep neurones the correlation was statistically significant for the deep receptive fields but not for the cutaneous ones.
Action Potentials↗
Structure-function relationships in identified afferent neurones.
The review deals with structure-function relationships in primary afferent and spinal cord neurones that were intracellularly injected with a marker substance (mostly HRP) after physiological identification. At the level of dorsal root ganglion (DRG) cells, there is a significant correlation between soma size and conduction velocity (or diameter) of the afferent fibre for most subpopulations of DRG cells, but the scatter of data is considerable, so that the size of a DRG cell soma cannot be predicted from the diameter of its axon or vice versa. The spinal terminations of primary afferent fibres are the best example of a relationship between structure and function, since most of the afferent units possess characteristic patterns of spinal arborization, e.g. the "flame-shaped arbors" of hair follicle afferents in lamina III of the dorsal horn, or the projection of nociceptive afferents onto lamina I. The morphological features of spinal cord neurones can be used only to a limited extent for functional identification. Thus, many SCT neurones can be recognized by their triangular dendritic tree and STT cells in lamina VII/VIII by their dendritic projection into the white matter. It is still not possible, however, to distinguish a nociceptive STT cell from a low-threshold mechanoreceptive one on the basis of morphological criteria.
Animals↗