Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also play a significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (CNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in CNS function which influence subsequent pain experience.

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Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence

Local effector functions of capsaicin-sensitive sensory nerve endings : involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides

Capsaicin-sensitive sensory neurons convey to the central nervous system signals (chemical and physical) arising from viscera and the skin which activate a variety of visceromotor and neuroendocrine reflexes integrated at various levels (intramurally in peripheral organs, at level of prevertebral ganglia, spinal and supraspinal level). Much evidence is now available that peripheral terminals of certain sensory neurons, widely distributed in skin and viscera have the ability to release, upon adequate stimulation, their transmitter content. In addition to the well-known "axon reflex" arrangement, the capsaicin-sensitive sensory neurons have the ability to release the stored transmitter also from the same terminal which is excited by the environmental stimulus. The efferent function of these sensory neurons is realized through the direct and indirect (i.e. mediated by activation of other cells) effects of released mediators. The action of released transmitters on postjunctional elements covers a wide range of effects which may have a physiological or pathological relevance. Development of drugs capable of controlling the sensory-efferent functions of the capsaicin-sensitive sensory neurons represent a new and very promising area of research for pharmacological treatment of various human diseases.

The sensory-efferent function of capsaicin-sensitive sensory neurons

By use of the indirect immunofluorescence technique the distribution of calcitonin gene-related peptide (CGRP)-like immunoreactivity (LI) has been analyzed in cervical and lumbar dorsal root ganglia of untreated and colchicine-treated rats. In addition, lumbar ganglia were examined 2 weeks after transection of the sciatic nerve. The occurrence of CGRP-positive cells in relation to ganglion cells containing substance P-, somatostatin-, galanin-, cholecystokinin (CCK)-, and vasoactive intestinal polypeptide (VIP)/peptide histidine isoleucin (PHI)-LI has been evaluated on consecutive sections as well as using elution-restaining and double-staining techniques.

Primary sensory neurons of the rat showing calcitonin gene-related peptide immunoreactivity and their relation to substance P-, somatostatin-, galanin-, vasoactive intestinal polypeptide- and cholecystokinin-immunoreactive ganglion cells.

Tachykinin receptors and tachykinin receptor antagonists

Calcitonin gene-related peptide (CGRP) in capsaicin-sensitive substance P-immunoreactive sensory neurons in animals and man: distribution and release by capsaicin.

Binding sites for synthetic human 125I-labeled calcitonin gene-related peptide (125I-CGRP) have been demonstrated in membranes of the human nervous system. Binding was high in the cerebellar cortex (1.35 +/- 0.27 fmol/mg of tissue; mean +/- SEM), spinal cord (1.06 +/- 0.27 to 1.27 +/- 0.23 fmol/mg), and nucleus dentatus (1.02 +/- 0.15 fmol/mg), intermediate in the inferior colliculus (0.80 +/- 0.14 fmol/mg) and substantia nigra (0.75 +/- 0.14 fmol/mg), low in the neocortex, globus pallidus, nucleus caudatus, hippocampus, amygdala, superior colliculus, thalamus, and hypothalamus (0.15-0.32 fmol/mg), and negligible in spinal and sympathetic ganglia and pituitary (less than 0.04 fmol/mg). Autoradiography showed distinct 125I-CGRP binding over the molecular and Purkinje cell layers of the cerebellar cortex and over the substantia gelatinosa posterior of the spinal cord. The highest levels of CGRP-like components were recognized in the dorsal part of the spinal cord and the pituitary gland. In the ventral part of the spinal cord as well as in the pituitary and thyroid glands, CGRP values were higher when measured by radioreceptorassay as compared to RIA, indicating that at least two CGRP-like components are present. The predominant CGRP-like peak on HPLC had the retention time of synthetic human CGRP. Immunohistochemistry revealed the presence of a dense plexus of CGRP immunoreactive nerve fibers in the dorsal horn of the spinal cord.

Calcitonin gene-related peptide and its binding sites in the human central nervous system and pituitary.

Simultaneous release of several tachykinins and calcitonin gene-related peptide from rat spinal cord slices.

Calcitonin gene-related peptide (CGRP) and calcitonin (CT) are secreted by medullary thyroid carcinoma (MTC). Relationships between extracellular calcium ([[Ca2+]e), cytosolic free calcium ([Ca2+]i) (as measured with fura-2), and secretion of immunoreactive CGRP and CT have been investigated in rat and human MTC cell lines. Rat MTC 6–23 cells responded to a rise in [[Ca2+]e from 0.5 to 3.0 mM with a transient increase of [Ca2+]i, and the secretion of CGRP and CT was raised from 19 ± 2 (mean ± SE) to 122 ± 28 pg rat CGRP/mg protein · min and from 33 ± 8 to 155 ± 42 pg rat CT/mg protein · min (P < 0.01). In the human MTC (TT) cell line, a rise of [[Ca2+]e from 0.5 to 3.0 mM did not affect [Ca2+]i, and the secretion of CGRP and CT remained unchanged at 7.0 ± 1.1 ng CGRP/ mg protein · min and 1.0 ± 0.1 ng CT/mg protein · min. However, when the plasma membrane was bypassed by electropermeabilization, the release of CGRP and CT was stimulated by calcium with an ED50 of 0.5 /μM and 0.3 μM, respectively. With ion...

Role of Cytosolic Free Calcium Concentration in the Secretion of Calcitonin Gene-Related Peptide and Calcitonin from Medullary Thyroid Carcinoma Cells

Human PTH (hPTH)-(3–84) and hPTH-(8–84) were synthesized in Escherichia (E.) coli when the cells were transformed with a multicopy plasmid in which the transcription of human preproPTH cDNA is directed by the E. coli lac promoter. PTH fragments were extracted from cells and purified by reverse phase HPLC. PTH bioactivity and PTH antagonist activity were estimated in a renal cytochemical bioassay. hPTH- (3–84) and hPTH-(8–84) exhibited less than 1% and less than 0.1%, respectively, of the biological activity of synthetic hPTH- (1–84). hPTH-(8–84) had 1% of the PTH inhibitory activity of synthetic [Nle8,18,Tyr34]bovine PTH-(3–34)amide, whereas hPTH-(3–84) was 100 times more active as a PTH inhibitor than the synthetic bovine PTH-(3–34) analog. The latter has so far been recognized as the most potent PTH antagonist in vitro. A 5-fold molar excess of hPTH-(3–84) over hPTH-(l–84) completely blocked the biological action of intact hPTH-(l–84) in the renal cytochemical bioassay. These findings suggest that the c...

Josef B. Petermann

Papers

Calcitonin gene-related peptide (CGRP) in capsaicin-sensitive substance P-immunoreactive sensory neurons in animals and man: distribution and release by capsaicin.

Calcitonin gene-related peptide and its binding sites in the human central nervous system and pituitary.

Simultaneous release of several tachykinins and calcitonin gene-related peptide from rat spinal cord slices.

Role of Cytosolic Free Calcium Concentration in the Secretion of Calcitonin Gene-Related Peptide and Calcitonin from Medullary Thyroid Carcinoma Cells

Inhibition of parathyroid hormone bioactivity by human parathyroid hormone (PTH)-(3-84) and PTH-(8-84) synthesized in Escherichia coli.