Heat and mechanical hyperalgesia induced by capsaicin. Cross modality threshold modulation in human C nociceptors.

Quantitative thermal and mechanical algometry was studied in 4 human subjects exposed to various concentrations of capsaicin administered topically to the skin of the palm or forearm. Treated skin patches were assessed for changes in heat pain threshold and in mechanical pain threshold at various controlled temperatures. The results showed that: (1) in addition to heat hyperalgesia, capsaicin consistently induces overt mechanical hyperalgesia; (2) thermal and mechanical hyperalgesias are linearly dependent on the log of capsaicin dose; (3) mechanical hyperalgesia is increased by increasing skin temperature; (4) mechanical hyperalgesia is abolished by cooling the skin to a point about 10 degrees C below the threshold for heat pain, a temperature that does not impair touch or sharp pain sensation. These sensory effects of capsaicin are mediated by C fibres, since dissociated A fibre block established by compression-ischaemia does not abolish either spontaneous pain or mechanical hyperalgesia. In addition, abolition of mechanical hyperalgesia by cooling persists during A fibre block. Cooling thus appears to act directly, presumably decreasing hyperexcitability of the C nociceptor. Hyperalgesia is also transiently depressed for at least 30 min during the postischaemic period, well beyond the duration of paraesthesiae or overt hyperaemia. Sensory changes identical to those induced experimentally by capsaicin have been observed in patients with a particular variety of neuropathic pain (ABC syndrome) and have been termed polymodal hyperalgesia and cross modality threshold modulation (Ochoa, 1986; Ochoa et al., 1987). Based on these overall observations, it is postulated here that the sensory abnormalities induced by capsaicin and those observed in this particular variety of patients relate to primary hyperalgesia and share a common mechanism in that the excitable receptor membrane of polymodal C nociceptors behaves as if it 'misreads' temperature.

Are hospital services rationed in New Haven or over-utilised in Boston?

The populations of New Haven and Boston are demographically similar and receive most of their hospital care in university hospitals, but in 1982 their expenditures per head for inpatient care were $451 and $889, respectively. The 685,400 residents of Boston incurred about $300 million more in hospital expenditures and used 739 more beds than they would have if the use rates for New Haven residents had applied. Most of the extra beds were invested in higher admission rates for medical conditions in which the decision to admit can be discretionary. The overall rates for major surgery were equal, but rates for some individual operations varied widely. These findings indicate that academic standards of care are compatible with widely varying patterns of practice and that medical care costs are not necessarily high in communities served largely by university hospitals. They also emphasise the need for increased attention to the outcome and cost implications of differences in practice styles.

Autoregulation of collagenase production by a protein synthesized and secreted by synovial fibroblasts: cellular mechanism for control of collagen degradation.

Conditioned medium taken from cultures of resting rabbit synovial fibroblasts contained a protein that prevented the synthesis of the neutral proteinase collagenase. Conditioned medium was concentrated 10-fold and placed on cultures of rabbit synovial fibroblasts along with an inducer of collagenase (phorbol myristate acetate or latex particles) and [3H]leucine. Collagenase production was measured by immunoprecipitation of culture medium with monospecific antibody. Gel filtration showed that the inhibitory factor had MrS of 12,500, 25,000-50,000, and 150,000, suggesting that the protein may exist as aggregates. Activity was destroyed by boiling, by trypsin, and by dithiothreitol. Production of the inhibitory protein was prevented by cycloheximide. Isoelectric focusing purified the protein 100- to 150-fold and revealed pIs in the range of 3.2-3.7. Glycosylation was demonstrated by binding to Con A-Sepharose. Our data indicate that rabbit synovial fibroblasts autoregulate collagenase production and suggest that the low levels of collagenase seen in resting cultures result from an active suppression of collagenase synthesis.

Monoclonal antibodies to cytoplasmic domains of the acetylcholine receptor.

Fourteen clonal hybridoma lines that secrete monoclonal antibodies (mabs) to the Torpedo acetylcholine receptor (AChR) have been isolated. When analyzed by an immunoreplica technique, two mabs recognized the alpha subunit, three reacted with the beta subunit, one reacted with the gamma chain, and five recognized the delta subunit. One mab failed to react with any of the subunits using this assay and two mabs recognized determinants found on both the gamma and the delta subunits. These were classified according to their reactivities with the membrane-bound Torpedo AChR. One category is comprised of mabs (including both anti-alpha mabs) that recognize extracellular epitopes. A second classification included mabs that are unable to bind the membrane-associated AChR. The third category is comprised of mabs directed against cytoplasmic epitopes of the AChR. The latter mabs, all of which recognize the gamma or delta subunits or both, bind only slightly to sealed, outside-out Torpedo vesicles. The binding is increased 10-20-fold by either alkaline extraction or treatment of the vesicles with 10 mM lithium diiodosalicylate but not by permeabilization of the vesicles with saponin. Three of the six mabs in this category react with frog muscle endplates but only if the cytoplasmic surface of the membrane is accessible.

Preparation of a biologically active rat prolactin devoid of antidiuretic activity.

Rat prolactin (NIH rPRL-B2) was purified using Sephadex chromatography and isoelectric focusing. SDS-gel electrophoresis of the original material showed a major band of 23K daltons, as well as several minor bands; the purified prolactin had a single 23K band. The original material contained 33 pg of immunoreactive vasopressin per 0.1 micrograms of material; vasopressin was not detectable in the purified material by either RIA or bioassay. The purified preparation had complete biological activity in a mammary gland bioassay and a receptor binding assay.

Abnormal spontaneous activity in single sensory nerve fibers in humans.

Spontaneous discharges generated in human motor nerve fibers have long been recognized, and their effects have been comfortably recorded from the muscle target with needle electrodes. Delay in documenting comparable phenomena from sensory fibers is explained by the need to record the abnormal activity directly from nerve fibers using intraneural microelectrodes. The hypothesis that a variety of positive sensory phenomena associated with nerve disease is the result of ectopic impulse generation from within the sensory unit can now be tested with microneurographic techniques. Research inaugurating microneurography in the study of positive sensory phenomena has yielded evidence of ectopic impulse generation from sensory units in subjects actually experiencing paresthesia or pain. The phenomenology of ectopic discharges in sensory fibers has been recorded with intraneural microelectrodes in: (1) transient postischemic paresthesia induced experimentally in otherwise normal nerves; (2) spontaneous paresthesia symptomatic to (probable) structural nerve pathology; and (3) in the sign of Tinel in traumatic neuromas.

Detergent extraction of a presumptive gating component from the voltage-dependent sodium channel.

A physiologically characterized radiolabeled neurotoxin complex obtained from venom of the scorpion Leiurus quinquestriatus has been used to identify detergent-solubilized presumptive sodium channel components in sucrose gradients. This toxin-binding component is found in extracts prepared from three sources of excitable membrane but appears to be absent from similar extracts prepared from nonexcitable membrane or from Torpedo californica membrane. Procedures that destroy the physiological activity of the Leiurus neurotoxin lead to a corresponding loss of toxin binding to the putative sodium channel component. The major component recognized by the Leiurus toxin sediments at 6.5 S. Scatchard analysis of quantitative binding experiments carried out in sucrose gradients shows approximately linear plots and indicates that the toxin recognizes a relatively small number of sites with a dissociation constant near 10 nM. Once formed, the channel element--toxin complex is quite stable. Experiments show diphasic dissociation kinetics with half-times near 70 hr and greater than 200 hr.

Central respiratory and circulatory depression caused by intravascular saxitoxin.

1 In cats anaesthetized with pentobarbitone and vagotomized, observations were made on the phrenic nerve action potential and the diaphragm electromyogram (EMG) at constant end-tidal Pco(2). Arterial blood pressure was stabilized by intravenous infusions of noradrenaline.2 Intravenous administration of saxitoxin (STX) initially abolished respiratory activity in the EMG and caused a slowing of oscillation in the central phrenic neurogram. Additional STX produced apneustic phrenic discharges followed by a progressive loss of nerve action potentials.3 The inspiratory centre in the medulla oblongata was stimulated electrically to evoke a sustained phrenic nerve discharge. STX, given intravenously, resulted in the elimination of spontaneous nerve activity without interfering with the evoked response.4 The cephalic intravascular infusion of STX into a carotid or vertebral artery depressed spontaneous respiratory activity while sparing EMG activity evoked by electrical stimulation of the intact phrenic nerve.5 Spontaneous respiratory discharge in the phrenic nerve was eliminated by smaller doses of STX administered intra-arterially than were required intravenously. In addition, onset of and recovery from neural silence occurred faster following intra-arterial injection of STX.6 Depressant effects on arterial blood pressure coincided with those on respiration when STX was given intra-arterially.7 An electrophysiological assay on frog sartorius muscle was used to measure STX in the cerebrospinal fluid. Levels of STX detected were proportional to amounts of the toxin infused intra-arterially.8 It is concluded that STX exchanges rapidly between blood and brain to bring about central depression and this adds to its peripheral paralytic actions.

Deacylated tRNA-phe binding to a reticulocyte ribosomal site for the initiation of polyphenylalanine synthesis.

The initiation of polyphenylalanine synthesis at low MgCl(2) concentration in the reticulocyte transfer system has been found to have a stringent requirement for deacylated tRNA(Phe). An initial poly-U-directed complex between deacylated tRNA(Phe) and ribosomes is formed. The onset of polyphenylalanine synthesis causes the rapid release of tRNA(Phe) from the complex. Thermal dissociation studies indicate that deacylated tRNA(Phe) and phenylalanyl-tRNA are bound to the same ribosomes. A total of three ribosomal tRNA binding sites is indicated.