Convergence of cutaneous and pelvic visceral nociceptive inputs onto primate spinothalamic neurons

The responses of 66 primate spinothalamic neurons to natural stimulation the the urinary bladder and testicle were studied with extracellular recording techniques in order to elucidate the neural basis for referral of visceral pain. Thirty-eight out of 53 cells located at the thoraco-lumbar junction or in sacral segments responded to noxious cutaneous stimuli, and 84% of these also exhibited phasic and/or tonic excitatory responses to distension of the urinary bladder. Seventeen out of 20 of these units, all located at the thoraco-lumbar junction, were excited by compression of the ipsilateral testicle. The response was graded with the compressive force. Excitatory responses to noxious heat and an irritant chemical (KC1) applied to the exposed testicular surface were also observed. Twelve sacral units having inputs from deep receptor of the tail exhibited mixed excitatory and inhibitory responses to bladder distension. A further 2 cells located at the thoracolumbar junction responded only to cutaneous tactile stimuli, and 13 cells located at the lumbosacral enlargement were tonically inhibited by bladder distension. It is concluded that spinothalamic neurons that convey nociceptive input from the skin may also respond to noxious visceral stimuli. Such viscero-somatic convergence provides a neural substrate for the phenomenon of cutaneous referral of visceral pain.     

Antinociceptive effects of ONO-9902, an enkephalinase inhibitor, after visceral stress condition in rats

PURPOSE: The present study was designed to examine the antinociceptive effects of orally administered ONO-9902, an enkephalinase inhibitor, on both somatic and visceral pain after visceral stress conditions. METHODS: Twenty six male rats were examined. Tail-flick (TF) and colorectal distension (CD) tests were used to determine somatic and visceral antinociceptive effects, respectively. Measurements were performed in rats under immediate post-stress conditions (group ST; n = 14) and in rats nor under stress conditions (group NST; n = 12). In the stressed group, the same device, CD, for visceral antinociceptive effects was used for visceral stress and was applied with an intracolonic pressure of 60 mmHg for 20 min after drug administration. The TF latency and CD threshold were measured before and at 30, 40, 50, 60 and 90 min after administration of ONO-9902 300 mg.kg-1 or distilled water. RESULTS: Orally administered ONO-9902 did not produce any changes in the % maximum possible effect (%MPE) in either TF or CD tests in the unstressed group. In the stressed group, %MPE in the CD test increased 18% and 31% at 30 and 40 min, respectively, after oral administration of ONO-9902 compared with the control group (P < 0.05). However, %MPE to TF test did not alter even after the CD-induced stress condition. CONCLUSION: These results suggest that ONO-9902 may have analgesic effects on visceral pain but not on somatic pain under immediate post-stress conditions.     

Role of the posterolateral nucleus of the cat thalamus in conducting peripheral and cortical polysensory influences]

The posterior lateral thalamic nucleus (LP) of the cat has separate inputs for ascending signals of different sensory and subcortical origin, as well as for cortifugal activity. With somatic stimuli, only non-specific and reticular signals come to LP. They are not directly involved in the genesis of evoked potentials (EP) in the parietal cortex (P) and the somatic zones I and II (SI and SII). With visual stimuli, specific and reticular impulses directly concerned with the formation of visual EPs in the P and the visual zone (VI) are projected to LP. The cortifugal action of VI, SI and SII influences the same modality in LP. The descending effect of P on visual and somatic signals in LP is actieved along autonomous pathways and consists in dissimilar types of direct (as in VI) and indirect (as in SI and SII) descending influences of different projection zones on impulses of the same modality in the given nucleus.     

Inadequate frameworks for understanding bodily homeostasis

Separate nervous systems, somatic and autonomic, were proposed to regulate the portion of the individual's life that is concerned with the external environment and the portion that is concerned with internal homeostasis. Regulation of the autonomic system by the CNS was assigned to the limbic system. Brainstem circuitry, between limbic and autonomic systems, was assigned to the supposedly nonspecific reticular formation. In fact, daily survival depends on integrated control of behavior and internal physiology. In mammals only the brain has the inbuilt programming for patterned co-ordination of these activities. The terms autonomic nervous system, limbic system and reticular formation are at odds with this patterned co-ordination. They should be abandoned and replaced with the term visceral neurons (afferent and efferent) and with reference to relevant specific-neural circuitry in the brain.     

Effects of kappa-opioid receptor agonists on responses to colorectal distension in rats with and without acute colonic inflammation

The objective of this study was to evaluate the effects of kappa-opioid receptor agonists on pressor and visceromotor responses to colorectal distension in awake, unrestrained rats, a model of visceral pain. Because visceral pain can be enhanced in the presence of inflammation, the study was conducted in rats that had been given either intracolonic saline or 5% acetic acid 6 hr before drug administration. We developed a method of staircase colorectal distension as a means of obtaining stimulus-response functions over a short period of time. Kappa-opioid receptor agonists, given i.v. in a cumulative dose paradigm, dose-dependently attenuated both the pressor and visceromotor responses to colorectal distension. In addition, all drugs tested also increased response threshold. The rank order of potency of the drugs tested was: CI977 > U69,593 > U50,488 > or = morphine > or = EMD61,753 > ICI204,448. Effective doses of these drugs were antagonized by naloxone, but not by either of two kappa-opioid receptor-selective antagonists (nor-binaltorphimine and 2-(3,4-dichlorophenyl)-N-methyl-N-(1-[3-isothiocyanate phenyl]-2-[1-pyrrolidinyl]ethyl)-acetamide). Acute inflammation of the colon did not lead to changes in the potency of the agonists tested. The present results provide further evidence that kappa-opioid receptor agonists significantly attenuate visceral nociception and, in conjunction with other information, suggest that a peripherally restricted kappa-opioid receptor agonist would be therapeutically effective in relieving visceral pain.     

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.     

Effects of gastric distension and electrical stimulation of dorsomedial medulla on neurons in parabrachial nucleus of rats

The effects of gastric distension and electrical stimulation of the dorsomedial medulla on neurons within the parabrachial nucleus (PB) were investigated electrophysiologically in urethane-chloralose anesthetized rats. Among 74 neurons tested, electrical stimulation of the nucleus of the solitary tract (NTS) excited 30 neurons (excitatory neurons) and inhibited 14 neurons (inhibitory neurons). Fourteen neurons increased and 12 neurons decreased their discharge rates in response to gastric distension. Twenty-two neurons responded to both electrical stimulation of the NTS and gastric distension. Both excitatory and inhibitory neurons showed either an increase or a decrease in discharge rate responding to gastric distension. Furthermore, three neurons that decreased their discharge rates and two neurons that increased their discharge rates during gastric distension also responded to intravenous administration of metaraminol indicating some effect of baroreceptor activation on the neural activity. The responses of another 49 neurons in the PB to electrical stimulation of area postrema and gastric distension were analyzed. Electrical stimulation of the AP excited 14 neurons and inhibited only one neuron. Five neurons increased and seven neurons decreased their discharge rates in response to gastric distension. Only one inhibitory neuron responded to gastric distension. These observations suggested that the PB neurons received gastric mechanoreceptive inputs from the NTS.     

Optimal conditions to induce rat adrenal medullary changes, such as pheochromocytoma, by nicotine

AIMS: Dihydrocodeine is metabolized to dihydromorphine via the isoenzyme cytochrome P450 2D6, whose activity is determined by genetic polymorphism. The importance of the dihydromorphine metabolites for analgesia in poor metabolizers is unclear. The aim of this study was to assess the importance of the dihydromorphine metabolites of dihydrocodeine in analgesia by investigating the effects of dihydrocodeine on somatic and visceral pain thresholds in extensive and quinidine-induced poor metabolizers. METHODS: Eleven healthy subjects participated in a double-blind, randomized, placebo-controlled, four-way cross-over study comparing the effects of single doses of placebo and slow-release dihydrocodeine 60 mg with and without premedication with quinidine sulphate 50 mg on electrical, heat and rectal distension pain tolerance thresholds. Plasma concentrations and urinary excretion of dihydrocodeine and dihydromorphine were measured. RESULTS: In quinidine-induced poor metabolizers the plasma concentrations of dihydromorphine were reduced between 3 and 4 fold from 1.5 h to 13.5 h after dosing (P < 0.005) and urinary excretion of dihydromorphine in the first 12 h was decreased from 0.91% to 0.28% of the dihydrocodeine dose (P < 0.001). Dihydrocodeine significantly raised the heat pain tolerance thresholds (at 3.3 h and 5 h postdosing, P < 0.05) and the rectal distension defaecatory urge (at 3.3 h and 10 h postdosing, P < 0.02) and pain tolerance thresholds (at 3.3 h and 5 h postdosing, P < 0.05) compared with placebo. Premedication with quinidine did not change the effects of dihydrocodeine on pain thresholds, but decreased the effect of dihydrocodeine on defaecatory urge thresholds (at 1.5 h, 3.3 h and 10 h postdosing, P < 0.05). CONCLUSIONS: In quinidine-induced poor metabolizers significant reduction in dihydromorphine metabolite production did not result in diminished analgesic effects of a single dose of dihydrocodeine. The metabolism of dihydrocodeine to dihydromorphine may therefore not be of clinical importance for analgesia. This conclusion must however, be confirmed with repeated dosing in patients with pain.     

Excitatory amino-acid receptors contribute to carotid sinus and vagus nerve evoked excitation of neurons in the nucleus of the tractus solitarius

To determine the role of excitatory amino-acid (EAA) receptors in afferent evoked excitation of neurons in the nucleus of the solitarius (NTS), responses of NTS neurons to activation of visceral afferent inputs were examined before and during iontophoretic application of the broad spectrum EAA receptor antagonist kynurenate (KYN). Iontophoretic application of KYN, at doses which attenuated glutamate but not substance P or acetylcholine evoked discharge, inhibited carotid sinus nerve (CSN) and vagus nerve evoked discharge. KYN attenuation of evoked responses was similar whether the evoked input was monosynaptic (CSN evoked discharge reduced by 50 +/- 6% (mean +/- SE; n = 5); vagus nerve evoked discharge reduced by 45 +/- 4%, n = 6) or polysynaptic (CSN evoked discharge reduced by 48 +/- 6%, n = 6; vagus nerve evoked discharge reduced by 43 +/- 3%, n = 8). Spontaneous action potential discharge rate was reduced during KYN iontophoresis in 6 cells (1.8 +/- 0.4 spikes/s vs. 0.7 +/- 0.2 spikes/s). Iontophoretic application of a structural analogue of KYN which has no EAA receptor antagonist properties, xanthurenic acid, had no effect on glutamate, CSN or vagus nerve evoked discharge. Iontophoretic application of KYN reduced the action potential discharge evoked by activation of the carotid body chemoreceptors by 52 +/- 2% in 5 cells tested. The results demonstrate that excitatory amino-acid receptors are involved in visceral afferent evoked activation of NTS neurons. Furthermore, since both mono- and poly-synaptic inputs were attenuated, these receptors appear to be utilized at multiple levels of afferent integration within NTS.     

Protein synthesis in chloroplasts. VII. Initiation of protein synthesis in isolated intact pea chloroplasts

The distribution and features of cardiovascular neurons (CVN) were studied in the brainstem of chloralose-anesthetized rats. Only neurons yielding an immediate response to carotid occulsion (CO) were considered as CVN. The criterion was deduced from the response patterns of cardiovascular afferent (carotid sinus nerve) and efferents (sympathetic and vagal nerves) during CO. Seventy-two CVN were identified and were observed to be mostly in the medullarly reticular formation and to some extent in the nucleus tractus solitarius and nucleus ambiguus. Fifty-five CVN (type A) decreased their firing rates in response to CO where 17 CVN (type B) increased their rates. Analyses of the time courses of their responses to CO revealed the convergence of the chemoreceptor and baroreceptor inputs onto some type A neurons. Electrical stimulation of the spinal cord evoked orthodromic responses in some neurons in both types. The evoked responses were blocked by CO in type A neurons whereas they were facilitated in those of type B. These results suggest that input from arterial baroreceptors, arterial chemoreceptors, and spinal ascending afferents is integrated within CVN.     

Cardiopulmonary sympathetic input excites primate cuneothalamic neurons: comparison with spinothalamic tract neurons

Stimulation of cardiopulmonary sympathetic afferent fibers excites thoracic and cervical spinothalamic tract (STT) cells that respond primarily to noxious somatic stimuli. Neurons in dorsal column nuclei respond primarily to innocuous somatic inputs, but noxious stimulation of pelvic viscera activates gracile neurons. The purpose of this study was to compare effects of thoracic visceral input on cuneothalamic and STT neurons. Stellate ganglia of 17 anesthetized monkeys (Macaca fascicularis) were stimulated electrically to activate cardiopulmonary sympathetic afferent fibers. Somatic receptive fields were manipulated with brush, tap, and pinch stimuli. Extracellular discharge rate was recorded for neurons antidromically activated from ventroposterolateral (VPL) thalamus. Stimulation of the ipsilateral stellate ganglion increased activity of 17 of 38 cuneothalamic neurons and of 1 gracilothalamic neuron with an upper body somatic field. Spinal cord transections showed that cardiopulmonary input to cuneothalamic neurons traveled in ipsilateral dorsal column and probably in dorsolateral funiculus. One of eight gracilothalamic neurons with lower body fields was inhibited by cardiopulmonary input, and none were excited. Stimulation of the ipsilateral stellate ganglion increased activity in 10 of 10 T3-T4 STT neurons. Evoked discharge rates, latencies to activation and durations of peristimulus histogram peaks were significantly less for cuneothalamic neurons compared with STT neurons. Furthermore, additional long latency peaks of activity developed in histograms for 6 of 10 STT neurons but never for cuneothalamic neurons. Contralateral cardiopulmonary sympathetic input did not excite cuneothalamic neurons but increased activity of 7 of 10 T3-T4 STT neurons. Most cuneothalamic neurons (24 of 31 cells tested) responded primarily to innocuous somatic stimuli, whereas STT neurons responded primarily or solely to noxious pinch of somatic fields. Neurons that responded to cardiopulmonary input most often had somatic fields located on proximal arm and chest. Results of this study showed that cardiopulmonary input was transmitted in dorsal pathways to cuneate nucleus and then to VPL thalamus and confirmed that STT neurons transmit nociceptive cardiopulmonary input to VPL thalamus. Differences in neuronal responses to noxious stimulation of cardiopulmonary sympathetic afferent fibers suggest that dorsal and ventrolateral pathways to VPL thalamus play different roles in the transmission and integration of nociceptive cardiac information.     

Electrophysiological and neuropharmacological study of tectoreticular pathways in lampreys

Tectoreticular (TR) cells along the diencephalic-mesencephalic border are the origin of prominent crossed and uncrossed pathways that project to the middle (MRRN) and posterior (PRRN) rhombencephalic reticular nuclei in juvenile and adult lampreys [I.C. Zompa, R. Dubuc, Diencephalic and mesencephalic projections to rhombencephalic reticular nuclei in lampreys, Brain Res. (1998) in press.]. This study investigated the synaptic contacts between TR axons and the reticular cells. Intracellular recordings were carried out in reticular neurones (n=124) while microstimulating the TR regions. Tectoreticular inputs were recorded in all reticular cells studied (248 PSPs); although stronger responses were evoked in the MRRN neurones. The majority of responses were excitatory, but increasingly mixed and inhibitory when recorded in the middle and caudal part of the reticular nuclei. The excitation had the shortest onset latencies and sharpest slopes measured in both reticular nuclei, while the inhibition was longer and smoother. The characteristics of TR inputs to different reticular cell types is also presented. The transmission of evoked responses was isolated to the crossed and uncrossed TR pathways by studying the effects of 1% Xylocaine ejections and surgical lesions. The TR inputs were transmitted to reticular cells through monosynaptic and polysynaptic contacts. The synaptic transmission involved excitatory amino acids, acting through AMPA and NMDA receptors, while the inhibition was glycinergic. Comparisons with other sensory systems in lampreys are discussed.     

Medullary swallowing-related neurons in the anesthetized cat

Swallowing-related neurons (SRNs) were recorded systematically in the medulla oblongata of urethane-anesthetized cats. The SRNs received orthodromic inputs from the superior laryngeal nerve (SLN) and showed transient changes in their activity synchronous with swallowing. These neurons could be divided into three types. Type I SRNs are sensory-relay neurons from the SLN in the nucleus of the tractus solitarius (NTS), type II are interneurons located diffusely in the parvocellular reticular formation ventral to the NTS, which received oligosynaptic inputs from the SLN, and type III are motoneurons in the nucleus ambiguus. Some type II neurons still showed the swallowing activity after the animals were paralysed, which suggests that they could be involved in the generation of swallowing outputs.     

Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4 complement and cooperate with each other sequentially during visceral neuron development

The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and neurotrophin-4 (NT4) are crucial target-derived factors controlling the survival of peripheral sensory neurons during the embryonic period of programmed cell death. Recently, NT3 has also been found to act in a local manner on somatic sensory precursor cells during early development in vivo. Culture studies suggest that these cells switch dependency to NGF at later stages. The neurotrophins acting on the developing placode-derived visceral nodose/petrosal (N/P) ganglion neurons are BDNF, NT3, and NT4. To assess their roles in development, we analyzed embryonic development in mice carrying a deletion in each of these genes, or combinations of them, and found that they are essential in preventing the death of N/P ganglion neurons during different periods of embryogenesis. Both NT3 and NT4 are crucial during the period of ganglion formation, whereas BDNF acts later in development. Many, but not all, of the NT3- and NT4-dependent neurons switch to BDNF at later stages. We conclude that most of the N/P ganglion neurons depend on more than one neurotrophin and that they act in a complementary as well as a collaborative manner in a developmental sequence for the establishment of a full complement of visceral neurons.     

The equivalent source technique and cortical imaging

Intrinsic neurons containing serotonin (5-HT) are involved in the regulation of gastrointestinal motor function and are also thought to be important in the modulation of visceral sensory function. We have evaluated the effect of a specific 5-HT3 antagonist (ondansetron, O) on visceral sensation and rectal compliance in a randomized, double-blind, cross-over, placebo (P) controlled study of O 16 mg 3 times/day, in healthy volunteers and patients with irritable bowel syndrome (IBS). Symptoms were also evaluated in the latter group. A 2-week run-in period was followed by two 2-week treatment arms of P and O, separated by a 2-week wash-out period. Twelve healthy subjects and 9 patients with IBS were recruited. Assessment was by daily symptom and bowel function diary, and physiological tests of anal manometry, rectal sensory testing to distension and electrical stimulation, and rectal compliance. Ten healthy subjects completed the entire study, and 6 IBS patients completed the diary card evaluation, including 5 who also completed the physiological evaluation. O caused significantly (p < 0.01) firmer stools when considering both subject groups together. In the healthy subjects no physiological parameters were altered by O. In IBS patients the rectal sensory threshold to electrical stimulation tended to increase with O (20 vs. 28 mA, P vs. O, median, p = 0.06) while the urge (80 vs. 60 ml, p = 0.05) and maximum tolerated volumes (130 vs. 90, p = 0.03) to distension tended to decrease with O. Patients with IBS experienced significantly fewer daily episodes of pain while on O (2 vs. 1, p = 0.03). Serotonin-3 antagonism (O) causes firmer bowel actions in all subjects, and may affect gut sensitivity and pain in patients with IBS.     

Interaction of intrathecally infused morphine and lidocaine in rats (part II): effects on the development of tolerance to morphine

BACKGROUND: There has been little information regarding the effects of local anesthetics on tolerance to opioids, although chronic use of combination of opioids and local anesthetics is popular for pain control. This study was designed to examine the effects of lidocaine on morphine tolerance to somatic and visceral antinociception. METHODS: Rats received a continuous intrathecal infusion of morphine (0.3-10 microg x kg(-1) x h(-1)), lidocaine (30-1000 microg x kg(-1). h(-1)), a combination of those, or saline. After 6- day infusion, intrathecal morphine challenge test (5 microg/10 microl) was performed, and time-response curve was constructed to assess the magnitude of tolerance. The tail flick (TF) test and colorectal distension (CD) test were used to measure somatic and visceral antinociceptive effects, respectively. RESULTS: Antinociceptive effects in the TF and CD tests caused by morphine challenge were reduced (P < 0.01) in the morphine infused groups. The magnitude of the tolerance was inversely associated with the amount of morphine infused. Lidocaine infusion induced no different change in the morphine challenge test from that seen in the saline infusion group. Development of tolerance was greater in morphine 3 microg x kg(-1) h(-1) than in morphine 0.75 microg x kg(-1) x h(-1) + lidocaine 150 microg x kg(-1) x h(-1) despite their similar antinociceptive effects during intrathecal infusion. The infusion of a low dose of morphine (0.3 microg kg(-1) x h(-1)) did not reduce the antinociceptive effects in the challenge test. CONCLUSION: Lidocaine in combination with morphine does not reduce tolerance to morphine nor develop cross-tolerance. The intrathecal infusion of morphine induced tolerance to somatic and visceral antinociception in a dose-dependent fashion.     

Brain stem reticular units: synaptic responses to stimulation within the ascending reticular pathways

When the ascending reticular axonal system is stimulated, the responses of distal structures (e.g., the cerebral cortex) appear to outlast the stimulus; these longlasting effects could reflect the intrinsic nature of the distal structure, or the response could reflect an interaction among the reticular cells which tends to prolong the effects of stimulation. To examine the latter hypothesis, single units with ascending axons (projecting units) were recorded in the cat rostral rhombencephalon in acute experiments conducted under halothane-nitrous oxide anesthesia. Stimulation of areas to or through which axons of reticular neurons projected (midbrain tegmentum and lower tectum, medial thalamus, and basal forebrain) produced a consistent and specific response which was elicited only from these areas: suppression of spontaneous activity which was typically elicited from several areas having ascending axons. One-half of these responses were accompanied by a short latency-single spike synaptic excitation. Stimulating areas more than 1.0 mm from the ascending trajectory never produced this response, whereas the number of responses was directly related to the number of projecting axons identified in any one experiment from a given site. Thus, the predominant effect of stimulating within the ascending axonal trajectory was suppression of spontaneous activity in the projecting units, not an 'en cascade' activation of these units; on the contrary, the only type of excitation encountered was a single, short latency spike. Therefore, any effects of stimulation within the ascending reticular pathway which appear to outlast the stimulus (as previously described in the literature) cannot be ascribed to a reverberating (excitatory) circuit among projecting units. A possible source of the synaptic responses of projecting units is a retrograde activation of collaterals interconnecting the reticular cells. If such interaction exists, it is specifically distributed among cells with ascending axons, as the responses were only observed in a very few units not identified by antidromic excitation; however, other evidence is adduced to support the belief that these few units were projecting units whose axons were beyond the reach of the stimulating electrodes. Futhermore, the axons may be bundled such that units with axons nearest that of a given projecting unit give rise to the most extensive synaptic interactions; the activation of these nearby axons suppresses spontaneous activity, while axons farther away have a greater possibility of being excitatory in nature. Should such a medium for interaction exist, reticular collateral interactions might be seen to exist specifically for the purpose of decreasing the activity of cells destined for similar rostral target structures.     

Chemosensitivity of nociceptive, mechanosensitive afferent nerve fibres in the guinea-pig ureter

The mechanosensitivity and chemosensitivity of afferent fibres were investigated in an in vitro preparation of the guinea-pig ureter. Electrophysiological recordings were obtained from 5 U-1 (low mechanical threshold, contraction-sensitive) and 74 U-2 units (high threshold). U-2 units had significant higher levels of spontaneous activity, lower conduction velocities, higher mechanical thresholds (U-1: 7 mmHg; U-2: 39 mmHg), less pronounced phasic responses and longer latencies in the response to distensions than the U-1 units. For chemical stimulation, guinea-pig urine (> 800 mosmol/L), bradykinin and capsaicin were applied intraluminally. The responses of U-1 units mainly corresponded to the contractions induced by the chemical stimulation. The vast majority of the U-2 units were excited by urine, bradykinin (threshold: 0.1-1 microM) and capsaicin (threshold: 0.03-0.3 microM). The responses to urine could be mimicked by high concentrations of potassium ions (> 200 mM), but not by an equiosmolar solution of NaCl, urea and mannitol. Chemical stimulation could also result in a transient sensitization of the U-2 units to mechanical stimuli. In the anaesthetized guinea-pig, pseudo-affective responses could be evoked by ureteric distension (threshold: 30-60 mmHg) and serosal application of capsaicin. Intraluminal application of urine in vivo did not evoke any reactions, suggesting that the responses of the U-2 units to urine might be due to an impaired barrier function of the urothelium in vitro. The data are in agreement with the hypothesis that U-2 units are visceral polymodal nociceptors. Since the U-1 units were also able to encode at least noxious mechanical stimuli, their involvement in visceral nociception cannot be excluded.     

Trigeminal-reticular connections: possible pathways for nociception-induced cardiovascular reflex responses in the rat

Cardiovascular regulatory neurons of the ventral medulla and pons are thought to have an important role in the mediation of trigeminal nociception-induced reflex cardiovascular responses. However, the neural pathways that link the spinal trigeminal nucleus with ventral medullary and pontine autonomic cell groups are poorly understood. The present study utilized injections of the highly sensitive anterograde tracer substance biotinylated dextran combined with immunocytochemistry for tyrosine hydroxylase, the synthesizing enzyme for catecholamines, to investigate the distribution and morphology of projections from the spinal trigeminal subnucleus caudalis to ventral medullary and pontine catecholaminergic cell groups. Injection of biotylinated dextran into the dorsal subnucleus caudalis produced dense anterograde labeling in dorsal regions of the medullary and pontine reticular formation including the dorsal medullary reticular field, the parvicellular reticular field, and the parvicellular reticular field pars anterior. In the ventral medullary and pontine reticular formation, light anterograde labeling tended to be distributed in close proximity to the distal dendrites of catecholaminergic neurons located in the C1, A1, and A5 regions. Injections of anterograde tracer into the dorsal medullary reticular field produced dense anterograde labeling in the ventral medullary and pontine reticular formation. Numerous terminal-like varicosities were observed in close proximity to catecholaminergic neurons located in the C1, A1, and A5 regions. These data suggest that trigeminal pain-induced reflex cardiovascular responses involve indirect projections that terminate in the dorsal medullary and pontine reticular formation before reaching ventral medullary and pontine catecholaminergic cell groups known to be involved in cardiovascular regulation.     

Intraesophageal balloon distension test in Chagas' disease patients with noncardiac chest pain

Patients with Chagas' disease often have chest pain as a prominent symptom. The objective of this study was to compare the results of intraesophageal balloon distension in chagasic and nonchagasic patients with chest pain not caused by coronary obstruction. We studied 40 patients with chest pain and angiographically normal coronary arteries, 25 with a positive serologic test for Chagas' disease (Chagas group, 16 women, mean age 53+/-10 years), and 15 with a negative serologic test (control group, 11 women, mean age 46+/-10 years). All patients had radiologic and endoscopic examinations of esophagus, stomach, and duodenum, esophageal manometry with the acid infusion test in the distal esophagus, and intraesophageal balloon distension. None of them had esophageal dilation or any signs of cardiovascular disease. A 25-mm-long latex balloon located 10 cm above the lower esophageal sphincter was inflated and deflated over a period of 10 sec at 1-ml increments of air until the subjects reported chest pain or to a maximum volume of 20 mi. The test caused chest pain in 14 subjects in the control group (93%) and in 12 in the Chagas' disease group (48%, P < 0.05). The mean volume of air that caused chest pain was 10+/-3 ml in the control group and 15+/-4 ml in the Chagas' disease group (mean+/-SD, P < 0.05). The maximum intraesophageal pressure during the examination was higher in Chagas' disease patients with chest pain during balloon distension (60 +/- 21 mm Hg) than in patients who did not have chest pain (37 +/-18 mm Hg, P < 0.05) and did not differ from the control group (48+/-16 mm Hg, P > 0.05). With the other examinations there was no difference between groups or between patients with or without chest pain during the balloon distension test. Although esophagitis was observed in 47% of patients in the control group and in 40% of the Chagas' disease group, the acid infusion test was positive in 27% of patients in the control group and in 4% of patients in the Chagas' disease group. We conclude that, as compared to a group of patients with similar chest pain, chagasic patients are less sensitive to esophageal distension. Thus, it is unlikely that their chest pain is related to esophageal mechanisms.