Effects of kappa opioid receptor-selective agonists on responses of pelvic nerve afferents to noxious colorectal distension

The aim of this study was to examine the effects of kappa-opioid receptor selective agonists on responses of mechanosensitive afferent fibers in the pelvic nerve. Single-fiber recordings were made from pelvic nerve afferents in the decentralized S1 dorsal root of the rat. A total of 572 afferent fibers in the S1 dorsal root were identified by electrical stimulation of the pelvic nerve; 252 (44%) responded to noxious colorectal distension (CRD; 80 mmHg). Of these 252 fibers that responded to CRD, 100 were studied further. All 100 fibers gave monotonic increases in firing to increasing pressures of CRD. Eighty-eight fibers had low thresholds for response (mean: 3 mmHg) and 12 fibers had high-thresholds for response (mean: 28 mmHg). Responses of 17 fibers also were tested after instillation of 5% mustard oil (MO) into the colon. The resting activity of 16/17 fibers significantly increased after MO instillation; 13 (77%) also exhibited sensitization of responses to graded CRD when tested 30 min after intracolonic MO instillation. The effects of kappa1-opioid receptor preferring agonists (U50,488H, U69,593 and U62,066), the kappa2-opioid receptor preferring agonist bremazocine, and the kappa3-opioid receptor preferring agonist naloxone benzoylhydrazone (nalBzoH) were tested on responses of 64 mechanosensitive afferent fibers to noxious CRD. All five agonists dose-dependently inhibited afferent fiber responses to noxious CRD. Doses producing inhibition to 50% of the control response to CRD did not differ among the five agonists, ranging from approximately 4 to 15 mg/kg. The effects of kappa1, kappa2, and kappa3 receptor agonists were attenuated by naloxone; two kappa-opioid receptor-selective antagonists were ineffective. There were no differences in the dose-response relationships of these drugs for fibers recorded from untreated and irritant-treated colons. Conduction velocities of the fibers remained unaffected after high doses of all tested agonists. In an in vitro study, U50,488 (10(-4) M) did not produce any significant change in the tension of colonic smooth muscle. These results document that responses of mechanosensitive pelvic nerve afferent fibers innervating the colon are inhibited by kappa-opioid receptor agonists having varying affinities for putative kappa-opioid receptor subtypes. The inhibitory effects of these drugs likely are mediated by an action at receptors associated with the afferent fibers. The receptor at which these effects are produced is kappa-opioid-like but clearly different from the kappa-opioid receptor characterized in the CNS and is perhaps an orphan receptor.     

Characterization of mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat

1. Single-unit activity was recorded from S1 sacral dorsal root afferent fibers in the anesthetized rat. A total of 364 afferent fibers were identified by electrical stimulation of the pelvic nerve and subsequently tested for response to colorectal distension (CRD) and urinary bladder distension (UBD). Sixty-seven percent (n = 244) of the fibers were unmyelinated C-fibers and 33% (n = 120) were thinly myelinated A delta-fibers. 2. In three initial experiments, 35 fibers were identified by pelvic nerve stimulation and tested for response only to CRD; none of these fibers responded to CRD. In 20 subsequent experiments, 329 pelvic nerve afferent fibers were tested for response to CRD and UBD. Thirty-four percent (n = 112) of the 329 fibers were unresponsive to noxious CRD (80 mmHg) or to UBD (slow filling < or = 100 mmHg), 44% (n = 146) responded to UBD, 16% (n = 53) responded to CRD, and 6% (n = 18) responded to mechanical stimulation of the anal mucosa. 3. Of the total of 53 pelvic nerve afferent fibers that responded to CRD, 43 (81%) were C-fibers (mean: 1.5 m/s) and 10 (19%) were A delta-fibers (mean: 4.7 m/s). Fifteen of the CRD-sensitive fibers had no resting activity, whereas 38 fibers exhibited some resting activity (mean: 2.6 imp/s). 4. Reproducibility of responses to repeated CRD (80 mmHg, 30s, 10 trials at 4-min intervals) was tested in 17 fibers. In 16, responses to repeated distension were reproducible without evidence of facilitation or inhibition of subsequent responses. One fiber gave greater responses during the 9th and 10th trials. 5. Responses to graded CRD were studied in 44 fibers. All fibers exhibited monotonic, increasing stimulus-response functions < or = 80 mmHg of distension. Thresholds for response of the 44 fibers were determined after extrapolation of the least-squares linear-regression line to the ordinate and varied between 0 and 40 mmHg. Two populations of pelvic nerve afferent fibers in the colon were apparent: low threshold (LT) afferent fibers had a mean threshold of 2.9 mmHg (range: 0-10 mmHg; n = 34) and high threshold (HT) afferent fibers had a mean threshold of 32.6 mmHg (range: 28.0-40.0 mmHg; n = 10). 6. Chemosensitivity to bradykinin (BK) was tested in nine LT fibers. Seven fibers responded to BK (0.1 to 100 micrograms/kg ia) and two fibers did not respond up to 100 micrograms/kg of BK. Responses to BK tested in three fibers were dose dependent.(ABSTRACT TRUNCATED AT 400 WORDS)     

Kinetic characterisation and solubilisation of gamma-hydroxybutyrate receptors from rat brain

The effects of single electrical shocks to myelinated A and unmyelinated C afferent fibers of perineal and limb somatic nerves on the reflex discharges in pelvic parasympathetic (L6/S1) efferent nerves to the bladder were examined in anesthetized central nervous system (CNS)-intact and acute spinal rats. When the bladder was empty, stimulation of perineal somatic inputs to the L6 and S1 segments from the perineo-femoral branch of a pudendal nerve produced excitatory A- and C-reflex discharge components in postganglionic parasympathetic efferent nerve branches on the bladder surface. When the bladder was expanded and pelvic efferent neurons were rhythmically active, additional inhibitory A- and C-reflex components could be seen. After acute spinal transection, the same stimuli elicited excitatory A- and C-reflex discharges of similar latency as those observed before the spinal transection, but were of larger amplitude and longer duration; resting activity in the pelvic nerve was low, and no evoked inhibitory reflex components could be observed. Electrical stimulation of afferents in the tibial nerve had no effect when the bladder pressure was low, but when the bladder was distended, early and late components of reflex inhibition and excitation of parasympathetic activity were visible in CNS-intact rats; these reflex responses were abolished following spinalization.     

The effects of aging on the rat bladder and its innervation

1) Measurements of the cystometrogram, of the responsiveness of bladder muscle to pelvic nerve efferent stimulation and of the sensitivity of the pelvic nerve afferents to pressure and volume during distensions have been made in the bladders of young adult (2-3 months) and aged (26-29 months) rats, anesthetized with mixtures of urethane and chloralose. 2) The pressure-volume relationship differed in young adult and aged rats. The bladders of the aged rats held up to nearly six times the volume of the young animals, and these volumes were accommodated at lower pressures in the aged animals. The pressure at which micturition contractions appeared was similar in young adult and aged animals. 3) The passive pressure associated with each of a series of distending volumes was recorded when a pelvic nerve was cut unilaterally. The distal cut end of this cut pelvic nerve was stimulated for 10 s at 20 Hz, using square wave pulses of 10 V and 1.0 ms. The active pressure-volume relationship was constructed from this data. Both the active and the passive relationships were shifted to the right in the aged animals, and it was evident that aging was associated with a reduction in the maximal pressure generated during pelvic nerve stimulation. Also the change in intravesical pressure induced by bladder contraction was less in aged animals. 4) The most sensitive mechanoreceptor afferents appear to have pressure and volume thresholds that do not change significantly during aging. While the distension-sensitive afferents in the pelvic nerve appear to have a similar sensitivity to intravesical pressure in young adult and aged rats, they were less able to monitor volume in the aged animals. The stimulus response relationship for volume was often less steep in the aged animals. 5) In this study, aging was shown to be associated with a large increase in bladder volume and a reduced sensitivity of pelvic nerve afferents to volume, and a reduced ability to raise bladder pressure during contraction of bladder smooth muscle. The changes in bladder function associated with aging are discussed.     

Re-intervention in the anal region

In 29 rats, responses evoked by pelvic and hypogastric nerve stimulation were recorded from postganglionic nerves to bladder and penis (clitoris). Responses to pelvic nerve stimulation had nonsynapsing and synapsing components. The nonsynapsing component was relatively large in main nerve to penis and small in lateral nerve to penis and nerves to bladder. Pelvic nerve fiber synapsing on pelvic ganglion neurons to bladder had a large subliminal fringe, while fibers synapsing on neurons supplying penis (clitoris) had a small subliminal fringe. Recruitment was greater in nerves to bladder and lateral nerve to penis (clitoris) compared to main nerve to penis (clitoris), indicating more synapsing fibers in the former nerves. Almost all hypogastric fibers to bladder were direct. A small subliminal fringe was demonstrated for hypogastric fibers synapsing on neurons supplying penis. No subliminal fringe was evident for the bladder. Pelvic and hypogastric nerve interaction on pelvic ganglion neurons could not be demonstrated with either single shock or tetanic trains of conditioning stimuli. With antidromic stimulation, conduction velocities of afferent fibers in pelvic nerve ranged from 0.15 m per sec to 2.9 m per sec. In hypogastric nerve they ranged from 0.35 m per sec to 2.8 m per sec.     

Pain from excitation of identified muscle nociceptors in humans

The technique of intraneural microstimulation (INMS) combined with microneurography was used to excite and to record impulse activity in identified afferent peroneal nerve fibers from skeletal muscle of human volunteers. Microelectrode position was minutely adjusted within the impaled nerve fascicle until a reproducible sensation of deep pain projected to the limb was obtained during INMS. During INMS trains of 5-10 s in duration and at threshold for sensation, volunteers perceived a well defined area of deep pain projected to muscle. Psychophysical judgements of the magnitude of pain increased with increasing rates of INMS between 5 and 25 Hz. Also, the area of the painful projected field (PF) evoked during trains of INMS of various duration but constant intensity and rate typically expanded with duration of INMS. The intraneural microelectrode was alternatively used to record neural activity originating from primary muscle afferents. Eight slowly adapting units with moderate to high mechanical threshold were identified by applying pressure within or adjacent to the painful PF. Conduction velocities ranged from 0.9 to 6.0 m/s, and fibers were classed as Group III or Group IV. Capsaicin (0.01%) injected into the RF of two slowly conducting muscle afferents (one Group III and one Group IV) produced spontaneous discharge of each fiber and caused intense cramping pain, suggesting that the units recorded were nociceptive. Our results endorse the concept that the primary sensory apparatus that encodes the sensation of cramping muscle pain in humans is served by mechanical nociceptors with slowly conducting nerve fibers. Results also reveal that muscle pain can be precisely localized, although the human cortical function of locognosia for muscle pain becomes blunted as a function of duration of the stimulus.     

Mechanosensitive afferent units in the hypogastric nerve of the cat

1. Recordings have been made from ninety single afferent units in the hypogastric and lumbar splanchnic nerves of the cat. 2. The majority of units examined had properties similar to those previously described in the splanchnic nerve: they were slowly adapting mechanoreceptors with one to six punctate mechanosensitive sites distributed mainly along blood vessels as they approached the viscera in peritoneal ligaments; they had a wide range of mechanical thresholds and conduction velocities in the range 0.5-24 m s-1. 3. Receptive fields were found over the bladder base or its peritoneal ligaments or both, on the uterus or broad ligament or both, on the colon or mesocolon or both, and in association with the ureter, vas deferens, prostate or pelvic fat pads. 4. Discharges from afferent units associated with the bladder were investigated during spontaneous (or reflex) bladder contractions, passive distensions, and tetanic contractions induced by electrical stimulation of the sacral spinal cord. The mean spike rates of the adapted (tonic) discharges, observed during distensions and induced tetani, differed over part of the range of intravesical pressures examined. Their behaviour is discussed in relation to the concept of 'in series' tension receptors within the bladder wall.     

Differential c-fos expression in the nucleus of the solitary tract and spinal cord following noxious gastric distention in the rat

c-Fos has been used as a marker for activity in the spinal cord following noxious somatic or visceral stimulation. Although the viscera receive dual afferent innervation, distention of hollow organs (i.e. esophagus, stomach, descending colon and rectum) induces significantly more c-Fos in second order neurons in the nucleus of the solitary tract and lumbosacral spinal cord, which receive parasympathetic afferent input (vagus, pelvic nerves), than the thoracolumbar spinal cord, which receives sympathetic afferent input (splanchnic nerves). The purpose of this study was to determine the contribution of sympathetic and parasympathetic afferent input to c-Fos expression in the nucleus of the solitary tract and spinal cord, and the influence of supraspinal pathways on Fos induction in the thoracolumbar spinal cord. Noxious gastric distention to 80 mmHg (gastric distension/80) was produced by repetitive inflation of a chronically implanted gastric balloon. Gastric distension/80 induced c-Fos throughout the nucleus of the solitary tract, with the densest labeling observed within 300 microns of the rostral pole of the area postrema. This area was analysed quantitatively following several manipulations. Gastric distension/80 induced a mean of 724 c-Fos-immunoreactive nuclei per section. Following subdiaphragmatic vagotomy plus distention (vagotomy/80), the induction of c-Fos-immunoreactive nuclei was reduced to 293 per section, while spinal transection at T2 plus distention (spinal transection/80) induced a mean of 581 nuclei per nucleus of the solitary tract section. Gastric distension/80 and vagotomy/80 induced minimal c-Fos in the T8-T10 spinal cord (50 nuclei/section), but spinal transection/80 induced 200 nuclei per section. Repetitive bolus injections of norepinephrine produced transient pressor responses mimicking the pressor response produced by gastric distension/80. This manipulation induced minimal c-Fos in the nucleus of the solitary tract and none in the spinal cord. It is concluded that noxious visceral input via parasympathetic vagal afferents, and to a lesser extent sympathetic afferents and the spinosolitary tract, contribute to gastric distention-induced c-Fos in the nucleus of the solitary tract. The induction of c-Fos in the nucleus of the solitary tract is significantly greater than in the viscerotopic segments of the spinal cord, which is partially under tonic descending inhibition, but is not subject to modulation by vagal gastric afferents. Distention pressures produced by noxious gastric distention are much greater than those produced during feeding, suggesting that c-Fos induction in the nucleus of the solitary tract to noxious distention is not associated with physiological mechanisms of feeding and satiety. The large vagal nerve-mediated induction of c-Fos in the nucleus of the solitary tract following gastric distension suggests that parasympathetic afferents contribute to the processing of noxious visceral stimuli, perhaps by contributing to the affective-emotional component of visceral pain.     

The inhibitory effect of nociceptin on the micturition reflex in anaesthetized rats

1. We have investigated the effect of nociceptin on the micturition reflex evoked by distension or topical application of capsaicin on the urinary bladder of urethane-anaesthetized rats. 2. Nociceptin produced a dose-dependent (3-100 nmol kg(-1) i.v.) transient suppression of the distension-evoked micturition reflex: its effect was not modified by guanethidine (68 micromol kg(-1) s.c.) nor by bilateral cervical vagotomy, alone or in combination, and by naloxone (1.2 micromol kg(-1) i.v.). 3. Nociceptin (100 nmol/kg i.v.) slightly (about 30%) inhibited the contractions of the rat bladder produced by pre- or postganglionic electrical stimulation of the pelvic nerve. 4. Nociceptin almost totally abolished the reflex component of the response to topical capsaicin (1 microg in 50 microl). 5. In the rat isolated bladder, submaximal contractions produced by electrical field stimulation were slightly reduced (25+/-4% inhibition) by 1 microM nociceptin. Nociceptin did not affect the contraction of the rat bladder induced by acetylcholine (10 microM) or ATP (1 mM). 6. These findings indicate that nociceptin exerts a naloxone-resistant suppression of the volume-evoked micturition reflex which involves inhibition of transmitter release from postganglionic bladder nerves. An inhibitory effect on bladder afferent nerves is also suggested.     

Relationship between afferent and central temporal patterns in the locust olfactory system

Odors evoke synchronized oscillations and slow temporal patterns in antennal lobe neurons and fast oscillations in the mushroom body local field potential (LFP) of the locust. What is the contribution of primary afferents in the generation of these dynamics? We addressed this question in two ways. First, we recorded odor-evoked afferent activity in both isolated antennae and intact preparations. Odor-evoked population activity in the antenna and the antennal nerve consisted of a slow potential deflection, similar for many odors. This deflection contained neither oscillatory nor odor-specific slow temporal patterns, whereas simultaneously recorded mushroom body LFPs exhibited clear 20-30 Hz oscillations. This suggests that the temporal patterning of antennal lobe and mushroom body neurons is generated downstream of the olfactory receptor axons. Second, we electrically stimulated arrays of primary afferents in vivo. A brief shock to the antennal nerve produced compound PSPs in antennal lobe projection neurons, with two peaks at an approximately 50 msec interval. Prolonged afferent stimulation with step, ramp, or slow sine-shaped voltage waveforms evoked sustained 20-30 Hz oscillations in projection neuron membrane potential and in the mushroom body LFP. Projection neuron and mushroom body oscillations were phase-locked and reliable across trials. Synchronization of projection neurons was seen directly in paired intracellular recordings. Pressure injection of picrotoxin into the antennal lobe eliminated the oscillations evoked by electrical stimulation. Different projection neurons could express different temporal patterns in response to the same electrical stimulus, as seen for odor-evoked responses. Conversely, individual projection neurons could express different temporal patterns of activity in response to step stimulation of different spatial arrays of olfactory afferents. These patterns were reliable and remained distinct across different stimulus intensities. We conclude that oscillatory synchronization of olfactory neurons originates in the antennal lobe and that slow temporal patterns in projection neurons can arise in the absence of temporal patterning of the afferent input.     

A prospective randomized administration of 5''-deoxy-5-fluorouridine as adjuvant chemotherapy for hepatocellular carcinoma treated with transcatheter arterial chemoembolization

Surgical microscopy and electrophysiological techniques were used to standardize the nomenclature for the pudendal nerve and sacral plexus according to their somatic axonal composition in the male rat. We conclude that the pudendal nerve is the segment running from the L6-S1 trunk to the sacral plexus, carrying efferent fibers to the coccygeus, internal obturator, ventral and dorsal bulbospongiosus, ischiocavernosus, external anal sphincter, and external urethral sphincter muscles, and afferent fibers from the penis, prepuce, scrotum, and ventral-proximal tail. The sacral plexus is the complex formed by the bridge-like structure connecting the pudendal nerve with the lumbosacral trunk, and two nerve branches emerging from it, one innervating the proximal half of the scrotal skin, and the other innervating the muscles at the base of the penis known as the motor branch. These branches are only considered as a part of the sacral plexus because they integrate axons from both the lumbosacral trunk and pudendal nerve. The gross anatomy of the pudendal nerve and sacral plexus has a main organization that was observed in 70% of cases, whereas the remaining 30% occurred in two variants. This nomenclature is appropriate to describe the pudendal nerve and sacral plexus in studies that involve them being lesioned or electrophysiologically analysed. A main additional finding was that two large afferent branches innervate the scrotum, one the proximal half and the other the distal half. As mentioned above, the proximal branch belongs to the sacral plexus, whereas the distal branch belongs to the pudendal nerve because all its axons travel to the cord via this nerve. Since stimulation or even manipulation of the scrotal branches resulted in the secretion of semen containing spermatozoa, it is suggested that scrotal afferents are involved in some way in the ejaculatory process, a topic that deserves further research.     

Effect of neonatal surfactant therapy on lung function at school age in children born very preterm

BACKGROUND: Involuntary detrusor contractions often cause irritative symptoms such as urgency and incontinence. A dog model for acutely induced variable bladder outlet resistance was developed to investigate the possible role of prostatic afferent nerve fibers in the development and maintenance of detrusor instability. METHODS: Fifty-eight mongrel dogs (weight range 19.5-36.5 kg) were divided into five groups: group I (n = 11) had surgically induced bladder outlet obstruction. Group II (n = 14) had urinary obstruction and bilateral sectioning of the lowest branches of the pelvic plexus supplying the prostate. Group III (n = 10) had prostate denervation only. Groups IV (n = 10) and V (n = 13) were sham-operated and controls, respectively. In the obstructed groups (I and II), an artificial urinary sphincter (length 4.5-6.0 cm) was placed around the bladder neck and connected to a reservoir placed subcutaneously to allow postoperative adjustments of urinary resistance. All dogs were evaluated at baseline and postoperatively at 1, 3, and 6 months with uroflowmetry, postvoid residual urine volume, cystometry as well as serum creatinine, and urinalysis. RESULTS: Occurrences of detrusor instability were not associated with prostatic denervation input. The mean peak flow rates decreased significantly in the obstructed groups at all follow-ups, but did not change significantly in the nonobstructed groups. Postoperatively, the mean maximum bladder capacity was significantly decreased for groups I and II only. However, a significant correlation between maximum bladder capacity and maximum detrusor pressure could not be detected at any time point in any of the groups. Mean postvoid residual urine volume varied considerably in all groups over time. Creation of a urinary model of infravesical obstruction was associated with considerable problems. CONCLUSIONS: In our dog model of bladder outlet obstruction, prostatic sensory nerve fibers appear not to be involved in detrusor instability. Surgical induction of a constant model of bladder outlet obstruction was difficult even in a large animal. The observations from the present study raise questions about the validity of obstructive urinary animal models.     

Mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat are polymodal in character

This report describes the chemical and thermal sensitivity of mechanosensitive pelvic nerve afferent fibers innervating the colon of the rat. A total of 51 fibers in the S1 dorsal root, identified by electrical stimulation of the pelvic nerve, were studied. An approximately 7 cm length of descending colon was isolated in situ to permit intracolonic perfusion and distension with Krebs solution. Reproducibility of responses to repetitive colorectal distension (CRD, 40 mmHg, 30 s, every 4 min) was documented. All fibers gave monotonic, incrementing responses to graded CRD (5 to 60 mmHg). Increases (n = 6) or decreases (n = 6) in pH of the perfusate failed to produce any change in resting activity or responses to CRD. Infusion of bile salts increased the resting activity of 6/6 fibers in a concentration-dependent manner, but did not affect the magnitude of responses to CRD. After intracolonic instillation of an inflammatory soup (bradykinin 10(-5) M, PGE2 10(-5) M, serotonin 10(-5) M, histamine 10(-5) M and KCl 10(-3) M), 13/22 fibers exhibited sensitization of responses to CRD. Seventy-three percent of 45 fibers tested responded to intracolonic perfusion of heated Krebs solution. The estimated threshold for response was 45 degreesC and response magnitude increased with the temperature. A smaller proportion (30%) of 37 fibers tested responded to intracolonic perfusion of cold Krebs solution. The estimated threshold for response was 28 degreesC. Of 36 fibers tested, 8 were activated by both heat and cold; typically, fibers activated by heat did not respond to cold. In a sample of 26 fibers tested for response to all three modalities of stimulation, 11 responded to mechanical, chemical and thermal stimuli; the remaining 15 responded to mechanical and either chemical or thermal stimulation. Changes in intracolonic pressure in response to chemical and thermal stimuli were also evaluated. Inflammatory soup and bile salts did not change intracolonic pressure; heat and cold produced a modest decrease and increase in muscle tension, respectively. These results document that mechanosensitive pelvic nerve afferent fibers are also chemosensitive and/or thermosensitive, supporting the notion that visceral mechanoreceptors in general are likely polymodal in character.     

Immunocytochemical co-localization of substance P and calcitonin gene-related peptide in afferent renal nerve soma of the rat

Substance P, calcitonin gene-related peptide and somatostatin immunoreactivities have been demonstrated in putative afferent renal nerve fibers in the rat. Utilizing retrograde-tracing and immunohistochemistry, we labeled afferent renal nerve soma throughout dorsal root ganglia T9 to L1. Most (85%) of afferent renal nerve perikarya were immunoreactive for calcitonin gene-related peptide, 21% had substance P immunoreactivity and none had somatostatin immunoreactivity. All renal afferents immunoreactive for substance P also contained calcitonin gene-related peptide. These results provide evidence that calcitonin gene-related peptide and substance P are present and co-localized in afferent renal nerves, and therefore, mediate transmission of afferent renal input to the spinal cord in the rat.     

Sexual activity and contraceptive use: the components of the decisionmaking process

The developmental role of carbohydrate markers in the genesis of neuronal networks was studied using leech sensory afferents as a model. Leech sensory afferents express a mannose-containing epitope on their cell surface that is recognized by monoclonal antibody Lan3-2. Previously, the elaboration of sensory arbors in the synaptic neuropil of CNS ganglia was experimentally shown to depend on this mannose marker. Sensory arbors were abolished by perturbing sensory afferents in the intact nervous system with Lan3-2 Fab fragments, a glycosidase, or mannose-BSA. To understand the cytological mechanisms underlying mannose-specific recognition for synaptogenesis, we have now studied the effects of antibody perturbation at the ultrastructural level in the sensory afferent target region. A characteristic signature of a normal sensory afferent is its profuse collateral branching, which, with ongoing development, is replaced by a single widened process, the sensory trunk, which possesses numerous synaptic vesicle clusters. The inhibition of mannose-specific recognition leads to a rapid, major reorganization of different stages of sensory afferent growth. Collateral branches at the distal growing region are reduced three- to fourfold. The pruned axons grow at an accelerated rate. Developmentally older sensory trunks experience a threefold reduction in synaptic vesicle clusters. These responses suggest that depriving sensory afferents of mannose-specific recognition aborts their synaptogenesis and causes them to resume behavior typical of tracking through axonal tracts. The current findings also suggest that the mannose marker, by promoting both collateral branching andthe proliferation of synaptic vesicle clusters, plays a critical role in two stages of sensory afferent synaptogenesis.     

Putative projection of phrenic afferents to the limbic cortex in humans studied with cerebral-evoked potentials

Respiratory sensations may rely in part on cortical integration of respiratory afferent information. In an attempt to study such projections, we recorded evoked potentials at scalp and cervical sites in 10 normal volunteers undergoing transcutaneous phrenic stimulation (0.1-ms square pulses, intensity liminal for diaphragmatic activation, series of 600 shocks at 2 Hz). A negative cerebral component of peak latency (12.79 +/- 0.54 ms; N13) was constant, and a negative spinal component (7.09 +/- 1.04 ms; N7) could also be recorded, all results being reproducible over time. Monitoring of cardiac frequency, skin anesthesia, and stimulation adjacent to the phrenic nerve made the phrenic origin of N7 and N13 the foremost hypothesis. Increasing stimulation frequency and comparison with median nerve stimulation provided arguments for the neural nature of the signals and their cerebral origin. Recordings from intracerebral electrodes in a patient showed a polarity reversal of the evoked potentials at the level of the cingulate gyrus. In conclusion, phrenic stimulation could allow one to study projections of phrenic afferents to the central nervous system in humans. Their exact site and physiological meaning remain to be clarified.     

Inconsistencies in the findings of child nutrition surveys in Bangladesh

We tested the hypothesis that adenosine excites nociceptive primary afferents innervating the knee joint. Neuronal recordings were made from fine nerve filaments innervating the knee joint in rats anaesthetized with pentobarbitone. Drugs were injected close-arterially (i.a.) or into the articular space (i.art.). We studied normal and chronically inflamed arthritic joints, the latter 14-21 days after a single intra-articular injection of Freund's Complete Adjuvant, performed under halothane anaesthesia. Adenosine injected i.a. caused delayed (approximately 10 s) excitation of the majority of polymodal C-fibre afferents, and had similar effects when injected directly into the joint. Adenosine triphosphate (ATP) had biphasic effects on discharge, a fast (<1 s) excitation was followed by a delayed increase similar to that seen with adenosine. The adenosine A1 receptor agonists N6-cyclopentyladenosine (CPA) and N-[(1S,trans)-2-hydroxypentyl] adenosine (GR79236) also excited the C-fibre afferents. The A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) antagonized the responses evoked by adenosine, CPA, and the delayed increase seen after ATP, indicating that excitation of the nociceptive afferents was mediated via adenosine A1 receptors. Adenosine and ATP evoked delayed excitatory effects of similar magnitude, regardless of whether or not the knee joint was chronically inflamed. The increased basal discharge observed in arthritic joints was unaffected by DPCPX, which implies that the increase in spontaneous activity associated with arthritis is unlikely to involve tonically released adenosine. The results support the hypothesis that adenosine excites primary afferent nociceptive nerve terminals in the rat knee joint, an effect mediated by adenosine A1 receptors. ATP, adenosine, and A1 receptors may play a role in generating the peripheral nociceptive (pain) signal.     

Facilitation of adrenal sympathetic efferent nerve activity induced by mechanical stimulation of teeth in the rat

The effects of afferent signals from the periodontal mechanoreceptors and muscle spindles of jaw-closing muscles on adrenal nerve activity were examined using anesthetized rats. The adrenal nerve activity increased with pressure stimulation of the teeth and by biting a wooden stick. However, after denervation of the periodontal ligament, the facilitation due to the stick-biting was not observed. These results indicate that periodontal afferents facilitate adrenal nerve activity.