Increase In Spontaneous Activity Research Articles

Primary afferents: In vitro characterization of the mechano- and chemo-sensitivity of pelvic nerve afferent fibers innervating the mouse colon

Primary afferent fibers in the pelvic nerves transmit noxious mechanical and chemical information from the distal colon/rectum, thereby placing this sensory pathway in a prominent position for targeting novel visceral analgesic drugs. However, the precise nature of pelvic afferent receptive endings has remained elusive because in vivo electrophysiologic techniques hinder access to receptive fields lying within the colon itself. We have adapted a previously described in vitro organ-nerve electrophysiologic technique to the mouse colon-pelvic nerve to better characterize the this crucial sensory pathway. Fine mucosal stroking (10mg) and circular stretch applied to afferent receptive fields discriminated four distinct classes of pelvic afferent: muscular afferents that responded only to stretch, mucosal afferents that responded only to stroking, muscular/mucosal afferents that responded to both stroking and stretch, and serosal afferents that responded to neither stimulus but could be activated by direct stimulation with von Frey probes. These afferents occur in relatively equal proportions (21%, 23%, 23%, 33%, respectively), are distributed throughout the distal 3 cm of the colon/rectum, and have small punctate receptive fields. We have also tested afferent chemosensitivity to focal application of an inflammatory soup (in μM: KCl 1000, histamine 0.5, serotonin 0.5, prostaglandin E2 0.5, bradykinin 0.5; 1 min). We have demonstrated that not only are mechanosensitive afferents activated by exposure to inflammatory soup, reflected by a sustained increase in spontaneous activity from a silent baseline to an average maximum firing rate (+ sem) of 23 + 7 Hz, but also are sensitized to subsequent mechanical stimulation following chemical exposure, with significant leftward shifts in the mechanical stimulus-response functions. These in vitro results bolster previous in vivo descriptions of pelvic nerve properties and provide the basis for studies on pelvic afferent contributions to changes occurring in animal models of visceral hyperalgesia.

Interferon-γ induces characteristics of central sensitization in spinal dorsal horn neurons in vitro

Hyperexcitability of spinal dorsal horn neurons, also known as ‘central sensitization’, is a component of pain associated with pathological conditions in the nervous system. The aim of the present study was to analyze if the pro-inflammatory cytokine, interferon-γ (IFN-γ), which can be released for extended periods of time in the nervous system during inflammatory and infectious events, can alter synaptic activity in dorsal horn neurons and thereby contribute to such hyperexcitability. Treatment of cultured dorsal horn neurons with IFN-γ for 2 weeks resulted in a significantly reduced clustering of α-amino-3-hydroxy-5-methylisoxazole (AMPA) receptor subunit 1 (GluR1) that was dependent on nitric oxide. The neurons displayed an increased frequency and amplitude of excitatory postsynaptic currents (EPSCs) upon IFN-γ treatment. Treated dorsal horn neurons also exhibited increased responsiveness to stimulation of dorsal root ganglia (DRG) axons in a two-compartment model. Furthermore, disinhibition by the GABA A receptor antagonist picrotoxin (PTX) significantly increased EPSC frequency and induced bursting in untreated cultures but did not significantly increase the frequency in treated neurons, which displayed bursting even without PTX. GABA A agonists reduced activity more strongly in treated cultures and immunochemical staining for GABA A receptors showed no difference from controls. Since GluR1-containing AMPA receptors (AMPARs) occur predominantly on inhibitory neurons in the dorsal horn, we suggest that the IFN-γ-mediated increase in spontaneous activity and responsiveness to DRG axon stimulation, decrease in sensitivity to PTX and tendency for EPSC bursting result from a reduced expression of GluR1 on these neurons and not from a reduction in active GABA A receptors in the network. IFN-γ thereby likely causes disinhibition of synaptic activity and primary afferent input in the dorsal horn, which consequently results in central sensitization.

Perinatal hypothyroidism effects on neuromotor competence, novelty-directed exploratory and anxiety-related behaviour and learning in rats

Thyroid hormone is essential for proper development of the mammalian CNS. Previous studies have documented a decrease in the ability of neonatal hypothyroid animals to learn and to habituate to maze tests and an increase in spontaneous activity. However, there is little information about the effects of perinatal (i.e. perinatal and postnatal) hypothyroidism on behaviour. The aim of the present work was to investigate the longitudinal effects of perinatal hypothyroidism on certain aspects of the behaviour in rats. Neuromotor competence was tested at 21, 40 and 60 days, novelty-directed exploratory behaviour and anxiety-related behaviour were evaluated at 40 and 60 days by means of the Boissier tests and associative learning ability was tested at 80 days by means of a step-through passive avoidance task. The persistence of the effects of perinatal hypothyroidism on psychomotor performance was highly dependent on the task examined. Perinatal hypothyroidism caused an increase of locomotor activity as revealed by the total distance travelled in the Boissier test and this increase also comprised a component of decreased anxiety-related behaviour. Methimazole-treated subjects also had higher head-dip scores than controls at 40 days while no differences were observed at 60 days. Finally, our results showed that methimazole-treated rats performed poorly in a passive avoidance learning task.

Neuropeptide expression following ligation of the ferret lingual nerve

Previous studies on the ferret inferior alveolar nerve found a close association between the spontaneous neural activity generated at a site of nerve injury, and the accumulation of neuropeptides in the injured axons. More recent electrophysiological studies on the lingual nerve revealed high levels of spontaneous activity 3 days after injury, a decline at 3 weeks and a late rise at 3 months. In the present study we have used immunocytochemical techniques to see whether this time course of spontaneous activity is again paralleled by an accumulation of neuropeptides. In 20 anaesthetised adult ferrets the left lingual nerve was ligated and sectioned distally, and the animals left to recover for 3 days, 3 weeks or 3 months. The tissue was processed using indirect immunofluorescence and image analysis was used to quantify levels of the neuropeptides; calcitonin gene-related peptide (CGRP), substance P (SP), vasoactive intestinal polypeptide (VIP), galanin (GAL), enkephalin (ENK) and neuropeptide Y (NPY). Immunoreactivity to all of the neuropeptides was present proximal to the ligature 3 days after injury, and these high levels of expression had decreased considerably by 3 weeks. By 3 months ENK and NPY expression had almost disappeared proximal to the ligature, but levels of CGRP, SP, VIP and GAL had increased slightly. This was also accompanied by an accumulation of all of the neuropeptides, except NPY, in the portion of nerve immediately distal to the ligature. This late accumulation of certain neuropeptides coincides with the increase in spontaneous activity seen in our previous electrophysiological studies and supports the suggestion that neuropeptides may play a role in the aetiology of sensory disorders after nerve injury.

Sensory properties of articular afferents following Mycoplasma arthritis in the chicken

The physiological properties of joint capsule mechanical nociceptors of monoarthritic chickens ( Gallus domesticus) were studied by recording the electrical activity from single C (Group IV) and A-delta (Group III) fibres dissected from the parafibular nerve. By injecting live Mycoplasma gallisepticum cultures into the ankle joint a typical mycoplasma arthritis was induced which was restricted to a single joint. During the early stage of the disease (7–21 days after infection) there was histopathological evidence of an acute synovitis and the fibres showed evidence of sensitisation. Sensitisation was observed in the significantly increased receptive field size, decreased response thresholds, increased response to joint movement both noxious and innocuous, but only in the C-fibres was there an increase in spontaneous activity. During the more chronic stage of the disease (49–56 days after infection) there was pathological evidence of prolonged synovitis but the sensory fibres responded normally to mechanical stimulation and joint movement. These changes in sensitivity of the joint capsule mechanical nociceptors provides peripheral neural evidence of possible pain experienced during the acute stage of the disease but not at the chronic stage when the disease might be in period of remission. The absence of any clear correlation between pathology and receptor activity demonstrates the difficulty of trying to predict nociceptive consequences in animals on the basis of histopathology.

Progesterone reverses the neuronal responses to hypoxia in rat nucleus tractus solitarius in vitro.

The nucleus tractus solitarius (NTS) is a relay nucleus that integrates peripheral chemoreceptor input in response to hypoxia and hence influences the generation of respiratory rhythm. Several studies have shown that administration of progesterone stimulates ventilatory responses to hypoxia. There is some evidence that this steroid hormone can act at the level of the arterial peripheral chemoreceptors, whereas its action in the central nervous system remains unclear. To investigate a possible central involvement during hypoxia, we studied the effect of progesterone on neuronal activities recorded extra- and intracellularly in the NTS using brainstem slices. Central chemosensitivity was tested by comparing synaptic activity and intrinsic electro-responsiveness of 38 neurones during normoxia and hypoxia. In more than two-thirds of neurones recorded, hypoxia elicited a hyperpolarisation, a decrease in the input resistance and a decrease in spontaneous activity. In the remaining neurones (n = 12) hypoxia elicited a depolarisation and an increase in spontaneous activity. In all neurones tested, synaptic potentials evoked by stimulation of the tractus solitarius were decreased by hypoxia. While progesterone (1 microM) had no effect under normoxic conditions, it partially reversed all hypoxic neuronal responses. This effect developed over 2-3 min and reversed within 5 min suggesting a non-genomic mechanism of action. Taken together these results suggest that progesterone interacts with the hypoxia-induced cellular signalling. We conclude that in the NTS, transmission of afferent signals is reduced by hypoxia and restored by progesterone administration. Such a mechanism may contribute to the stimulation of breathing in response to hypoxia observed following progesterone administration in vivo.

Spontaneous discharge and response characteristics of central otolith neurons of rats during postnatal development.

To study the developmental profile of otolith-related vestibular nuclear neurons, their spontaneous activities and response dynamics were examined in decerebrate rats aged seven, 14, 21 and 84 (adult) days. Extracellular recordings were performed in the lateral and descending vestibular nucleus of animals held at the stationary position in the earth-horizontal or subjected to constant velocity off-vertical axis rotation, which selectively stimulates the otolith receptors. All neurons displayed sinusoidal position-dependent modulation in discharge rate, indicating their capability in coding spatial information during low-frequency head movement. Some neurons showed a full-cycle response to off-vertical axis rotation (non-clipped), while other neurons were silenced in discharge during parts of each rotary cycle (clipped). In seven-day-old rats, three-quarters of the responsive neurons sampled were clipped and the proportion progressively decreased to less than one-quarter in adult rats. In each age group, the clipped neurons discharged in approximately 60% of the stimulus cycle. Response gains of the neurons increased with age, reaching a plateau from 21 days of age for clipped neurons and 14 days for non-clipped neurons. The clipped neurons demonstrated higher response gains than the non-clipped neurons at or beyond 21 days of age. Spontaneous activities of the neurons at the stationary and earth-horizontal positions were analysed in relation to their response gains; a positive correlation was observed from 14 days of age onwards. Both types of neurons showed progressive increase in spontaneous activity as the rats matured, though the clipped neurons exhibited significantly lower resting rates than the non-clipped neurons at each of the age groups studied. Some neurons that responded to off-vertical axis rotation were not spontaneously active at the stationary position, but the proportion of these decreased significantly with age. The coefficient of variation of each age group showed a bimodal distribution, thereby allowing spontaneously active neurons to be assigned as regular or irregular. Though the vast majority of both the clipped and non-clipped neurons showed irregular discharge patterns at seven days of age, the overall population became more regular as the rats matured. Irregular neurons of young rats exhibited phase-stable and phase-shift responses, while those of older rats showed only the phase-stable response. This distinction was not observed amongst regular neurons over the ages studied. Our results reveal features of central otolith neurons that can be taken as signs of maturation during the first three postnatal weeks. These neuronal features provide the framework for the analysis of behaviours mediated by the otolith system during postnatal maturation.

Inhibition Suppresses Transmission of Tonic Vibrissa-Evoked Activity in the Rat Ventrobasal Thalamus

Previous studies have demonstrated that tonic responses of trigeminal ganglion neurons to maintained whisker deflections are transformed to mainly phasic responses in thalamocortical neurons. The high tonic responsiveness of thalamic reticular neurons suggests that thalamic inhibition may contribute to this suppression of tonic activity. To test this hypothesis we recorded responses of thalamocortical neurons in the ventroposterior medial (VPm) nucleus to 200 and 400 msec sustained whisker deflections during simultaneous microiontophoresis of the GABA receptor antagonists bicuculline and phaclofen. Under control conditions, VPm units responded to deflection plateaus with mean activities of only 18 spikes/sec, compared with 16 spikes/sec spontaneous firing. A minority of cells (5/19) had significantly greater plateau than spontaneous activity, and these cells were classified as tonic; the other 14/19 were considered phasic. Under GABA receptor antagonism, however, mean plateau activity increased to 53 spikes/sec compared with 30 spikes/sec spontaneous activity, and 7 of the 14 phasic units became tonically responsive. Increases in plateau activity were significantly greater, by both absolute and relative measures, than increases in spontaneous activity. Transient responses to stimulus onsets and offsets also increased in magnitude 4.0- and 2. 9-fold, attributable mainly to their increased duration. These data indicate that VPm neurons receive tonic excitatory inputs that under normal conditions are masked by inhibition. Suppression of tonic activity in VPm by inhibitory thalamic reticular neurons may reduce tonic inhibition in cortical layer IV circuits, preserving their responsiveness to transient signals.

Short-term potentiation of miniature excitatory synaptic currents causes excitation of supraoptic neurons.

Magnocellular neurons (MCNs) of the hypothalamic supraoptic nucleus (SON) secrete vasopressin and oxytocin. With the use of whole-cell and nystatin-perforated patch recordings of MCNs in current- and voltage-clamp modes, we show that high-frequency stimulation (HFS, 10-200 Hz) of excitatory afferents induces increases in the frequency and amplitude of 2,3-dioxo-6-nitro-1,2,3, 4-tetrahydrobenzo(f)quinoxaline-7-sulfonamide (NBQX)-sensitive miniature excitatory postsynaptic currents (mEPSCs) lasting up to 20 min. This synaptic enhancement, referred to as short-term potentiation (STP), could be induced repeatedly; required tetrodotoxin (TTX)-dependent action potentials to initiate, but not to maintain; and was independent of postsynaptic membrane potential, N-methyl-D-aspartate (NMDA) receptors, or retrograde neurohypophyseal neuropeptide release. STP was not accompanied by changes in the conductance of the MCNs or in the responsiveness of the postsynaptic non-NMDA receptors, as revealed by brief application of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate. mEPSCs showed similar rise times before and after HFS and analysis of amplitude distributions of mEPSCs revealed one or more peaks pre-HFS and the appearance of additional peaks post-HFS, which were equidistant from the first peak. STP of mEPSCs was not associated with enhanced evoked responses, but was associated with an NBQX-sensitive increase in spontaneous activity of MCNs. Thus we have identified a particularly long-lasting potentiation of excitatory synapses in the SON, which has a presynaptic locus, is dissociated from changes in evoked release, and which regulates postsynaptic cell excitability.

Degradation of stimulus selectivity of visual cortical cells in senescent rhesus monkeys

Human visual function declines with age. Much of this decline is probably mediated by changes in the central visual pathways. We compared the stimulus selectivity of cells in primary visual cortex (striate cortex or V1) in young adult and very old macaque monkeys using single-neuron in vivo electrophysiology. Our results provide evidence for a significant degradation of orientation and direction selectivity in senescent animals. The decreased selectivity of cells in old animals was accompanied by increased responsiveness to all orientations and directions as well as an increase in spontaneous activity. The decreased selectivities and increased excitability of cells in old animals are consistent with an age-related degeneration of intracortical inhibition. The neural changes described here could underlie declines in visual function during senescence.

Neurophysiologic Mechanisms of Tinnitus

Research over the past decade has provided new insights into the neural mechanisms likely to produce the false percepts of sound associated with tinnitus. These insights have emerged mainly as a result of electrophysiologic studies, examining changes in brain activity, and behavioral studies, examining changes in perception, in animals that have been treated with well-known tinnitus inducers such as salicylates, quinine, and intense sound. The available evidence, based on electrophysiologic studies, suggests that tinnitus is associated with disturbances in spontaneous neural activity in the auditory system. These abnormalities include increases in spontaneous activity (hyperactivity), changes in the timing of neural discharges (i.e., the temporal firing properties of neurons), and an increase in bursting activity of neurons. Parallel studies using behavioral testing methods have demonstrated that agents, which produce these neural changes, also cause tinnitus in animals. This article reviews the literature concerned with both behavioral evidence for tinnitus in animal models and the associated changes that occur at peripheral and central levels of the auditory system.

Acute inflammation differentially alters the activity of two classes of rat spinal visceral nociceptive neurons

Quantitative neurophysiological studies have identified the presence of at least two spinal neuron populations (ABRUPT and SUSTAINED) which are excited by the noxious visceral stimulus colorectal distension (CRD). The present study examined the effects of acute colorectal inflammation on the activity of dorsal horn neurons in decerebrate, cervical spinal cord-transected male rats. Extracellular recordings were made using tungsten microelectrodes and inflammation was produced by intracolonic instillation of turpentine (25% solution). The total activity of SUSTAINED neurons during CRD increased starting one hour after turpentine instillation whereas the total activity of ABRUPT neurons during CRD, as a group, was unaffected during the two hours of study. Increases in total activity during CRD correlated with increases in spontaneous activity. These observations further support that visceral nociception travels by a dual pathway and suggest a predominant role for SUSTAINED neurons in the signaling of visceral pain-related events.

Cisplatin-induced increases in spontaneous neural activity in the dorsal cochlear nucleus and associated outer hair cell loss.

Tinnitus is one of the consequences of cisplatin chemotherapy, but its underlying mechanisms are not well understood. Since it has been shown that cisplatin causes outer hair cell loss, it is possible that loss of these cells might induce tinnitus by increasing spontaneous activity in the central auditory system. To test this possibility, the present study examined the effects of cisplatin treatment on cochlear hair cells and on spontaneous neural activity in the dorsal cochlear nucleus of hamsters. Recordings, carried out approximately 1 month after cisplatin treatment, demonstrated significant increases in spontaneous activity across broad regions of the dorsal cochlear nucleus relative to levels in saline-treated controls. Histological results showed that cisplatin-treated animals also displayed dramatic loss of outer hair cells over most of the basal turn of the cochlea. Inner hair cells remained intact, although some evidence of damage to their stereocilia was evident. These findings indicate that cisplatin treatment causes abnormalities in spontaneous activity in the dorsal cochlear nucleus that are associated with widespread damage to outer hair cells. However, since some damage to inner hair cells was also observed, the role of inner hair cell injury in contributing to higher spontaneous activity cannot be ruled out.

Spontaneous Firing Activity of Cortical Neurons in Adult Cats with Reorganized Tonotopic Map Following Pure-tone Trauma

We hypothesized that moderate sensorineural hearing loss resulting from acoustic trauma would cause (i) a change in the cortical tonotopic map, (ii) an increase in spontaneous activity in the reorganized region and (iii) increased inter-neuronal synchrony within the reorganized part of the cortex. Five kittens were exposed to a 126 dB sound pressure limit tone of 6 kHz for 1 h at both 5 and 6 weeks of age. Recordings were performed 7-16 weeks after the exposure. Auditory brainstem response thresholds for frequencies above 12 kHz were increased by 30 dB on average relative to those in normal cats. Tonotopic maps in the primary auditory cortex were reorganized in such a way that the area normally tuned to frequencies of 10-40 kHz was now entirely tuned to 10 kHz. Spontaneous firing rates were significantly higher in reorganized areas than in normal areas. In order to test for changes in inter-neuronal synchrony, cross-correlation analysis was done on 225 single-unit pairs recorded in the traumatized cats. For the single- and dual-electrode pairs there was no significant difference in peak cross-correlation coefficients for the firings of simultaneously recorded cells between normal and reorganized areas. However, the percentage of correlations that differed significantly from zero was higher in the reorganized area than in the normal area. This suggests a potential correlation between cortical reorganization, increased spontaneous firing rate and inter-neuronal synchrony that might be related to tinnitus found in high-frequency hearing loss induced by acoustic trauma.

Effects of GABA receptor antagonist on trigeminal caudalis nociceptive neurons in normal and neonatally capsaicin-treated rats.

We have recently demonstrated that significant increases in cutaneous mechanoreceptive field (RF) size and spontaneous activity occur in nociceptive neurons of trigeminal subnucleus caudalis (Vc, the medullary dorsal horn) of adult rats depleted of C-fiber afferents by neonatal treatment with capsaicin. These neuronal changes in capsaicin-treated (CAP) rats are suggestive of central neuroplasticity and involve N-methyl-D-aspartic acid (NMDA) receptor mechanisms. The present study examined whether the GABA(A) receptor antagonist bicuculline (BIC) or the GABA(B) receptor antagonist 2-hydroxysaclofen (SAC) can influence the RF properties and activity of Vc nociceptive neurons classified as either nociceptive-specific or wide-dynamic range in CAP adult rats or in neonatally vehicle-treated (CON) rats. C-fiber depletion was confirmed in the CAP rats by a significant decrease in plasma extravasation of Evans blue dye in a skin area receiving topical application of mustard oil, a small-fiber excitant and inflammatory irritant. As previously reported, marked increases in cutaneous RF size and spontaneous activity occurred in Vc nociceptive neurons of adult CAP rats, compared with CON rats. GABA(A) receptor blockade by BIC (i.t.) in CON rats produced a significant increase in spontaneous activity and in pinch RF size and tactile RF size (or appearance of a tactile area in the RF of nociceptive-specific neurons), as well as a significant lowering of the mechanical threshold and a significant enhancement of responses to pinch stimuli applied to the RF. In CAP rats, GABA(A) receptor blockade also produced significant changes similar to those documented in CON rats, except for a paradoxical and significant decrease in pinch RF size and no noticeable changes in responses to pinch stimuli. GABA(B) receptor blockade by SAC (i.t. ) did not produce any significant changes in Vc nociceptive neurons in either CON or CAP rats. These results suggest that GABA(A) receptor-mediated inhibition may be involved in maintaining the functional expression of Vc nociceptive neuronal properties in normal conditions, and that in animals depleted of their C-fiber afferents, some features of this GABA(A) receptor-mediated modulation may be disrupted such that a GABA(A) receptor-mediated excitation is manifested.

Mechanosensitive properties of gastric vagal afferent fibers in the rat.

Single, teased fiber recordings were made from the decentralized right cervical vagus nerve (hyponodal) of the rat. A total of 67 afferent fibers that responded to gastric distension (GD) were studied: 9 fibers were stimulated by phasic balloon GD, 58 by more natural fluid GD. All balloon GD-responsive fibers had resting activity (3.1 imp/s), and 57/58 fluid GD responsive fibers had resting activity (1.3 imp/s). All balloon GD-responsive fibers exhibited a dynamic response to phasic distension followed by slow adaptation, whereas fluid GD-responsive fibers exhibited increasing responses as intragastric pressure increased, followed typically by slow adaptation. Responses to graded GD were studied in all fibers, and all gave increasing responses to increasing pressures (5-60 mmHg). Thresholds for response varied between 0 and 18 mmHg. Mean response thresholds for two durations of fluid GD (30 and 60 s) were 5.6 and 3.9 mmHg; the mean response threshold to phasic balloon GD (30 s duration) was 5.3 mmHg. The potential sensitizing effect of platelet activating factor (PAF, 50 or 100 ng. kg(-1). min(-1) for 20 min) infused into the gastric artery was studied in 20 fibers. Fifteen fibers exhibited an increase in spontaneous activity; intragastric pressure also slightly increased during PAF infusion. The increase in activity produced by PAF was attenuated in the presence of the PAF receptor antagonist WEB 2086. After PAF-induced acute inflammation of the stomach, three of five fibers studied did not exhibit any change in response to graded GD. The present study characterized distension-sensitive afferent fibers in the right cervical vagus innervating the stomach of the rat by balloon GD and fluid GD. The results document that all distension-sensitive gastric vagal afferent fibers encoded the intensity of GD, but none had response thresholds in what might be considered the noxious range. PAF infusion activated mechanosensitive gastric vagal afferent fibers, but acute inflammation produced by PAF did not sensitize responses to GD.

Evidence for homeostatic adjustments of rat somatosensory cortical neurons to changes in extracellular acetylcholine concentrations produced by iontophoretic administration of acetylcholine and by systemic diisopropylfluorophosphate treatment

We describe the responses of single units in the awake (24 cells) or urethane-anesthetized (37 cells) rat somatosensory cortex during repeated iontophoretic pulses (1.0 s, 85 nA) of acetylcholine, both before and after systemic treatment with the irreversible acetylcholinesterase inhibitor diisopropylfluorophosphate (i.p., 0.3–0.5 ld 50). The time-course of the response to acetylcholine pulses differed among cortical neurons but was characteristic for a given cell. Different time-courses included monophasic excitatory or inhibitory responses, biphasic (excitatory–inhibitory, inhibitory–excitatory, excitatory–excitatory, and inhibitory–inhibitory), and triphasic (excitatory–excitatory–inhibitory, inhibitory–inhibitory–excitatory, and inhibitory–excitatory–inhibitory) responses. Although the sign and time-course of the individual responses remained consistent, their magnitude fluctuated across time; most cells exhibited either an initial increase or decrease in response magnitude followed by oscillations in magnitude that diminished with time, gradually approaching the original size. The time-course of the characteristic response to an acetylcholine pulse appeared to determine direction and rate of change in response magnitude with successive pulses of acetylcholine. Diisopropylfluorophosphate treatment, given 1 h after beginning repeated acetylcholine pulses, often resulted in a gradual increase in spontaneous activity to a slightly higher but stable level. Superimposed on this change in background activity, the oscillations in the response amplitude reappeared and then subsided in a pattern similar to the decay seen prior to diisopropylfluorophosphate treatment. Our results suggest that dynamic, homeostatic mechanisms control neuronal excitability by adjusting the balance between excitatory and inhibitory influences within the cortical circuitry and that these mechanisms are engaged by prolonged increases in extracellular acetylcholine levels caused by repeated pulses of acetylcholine and by acetylcholinesterase inhibition. However, this ability of neurons in the cortical neuronal network to rapidly adjust to changes in extracellular levels of acetylcholine questions the potential efficacy of therapeutic treatments designed to increase ambient levels of acetylcholine as a treatment for Alzheimer's disease or to enhance mechanisms of learning and memory.

Autotransplantation for Parkinson's disease goes a step further.

Autotransplantation for Parkinson's disease goes a step further.

An investigation of the neurophysiologic mechanisms of tourniquet-related pain: Changes in spontaneous activity and receptive field size in spinal dorsal horn neurons

Background and Objectives. Several theories have been proposed for the pain resulting from the nerve compression and ischemia associated with maintaining the inflation of a pneumatic tourniquet on an extremity. This investigation observes changes in the spontaneous activity and receptive field (RF) size of spinal dorsal horn neurons during tourniquet-related nerve compression and ischemia. Methods. Forty-eight pentobarbital-anesthetized rats were prepared for single-unit spinal dorsal horn cell recording utilizing an in vivo extracellular technique. Cells were characterized as either low threshold mechanoreceptor (LTM) neurons, wide dynamic range (WDR) neurons, or high threshold nociresponsive (NR) neurons based on their response to light touch (brush), non-noxious pressure, or noxious pinch. Receptive fields were carefully mapped. A 1 × 9 cm pneumatic tourniquet (Hokanson, Inc., Seattle, WA) was then applied to the animals' hind limb thigh and inflated to 300 mm Hg for 60 minutes. Throughout the 60-minute tourniquet inflation period, spontaneous activity, cell firing rate response characteristics, and RF size were carefully monitored. Results. Twenty-three cells in 20 animals were characterized and monitored: 8 LTM, 6 WDR, and 9 NR neurons. Receptive fields were distal to the tourniquet cuff for 16 cells and proximal for 7 cells. Low threshold mechanoreceptor neurons demonstrated little spontaneous activity prior to tourniquet inflation in the absence of RF stimulation. The RF size for all LTM neurons decreased or became silent during the tourniquet inflation period. The RF size increased in two of six WDR neurons with two cells demonstrating a progressive increase in intermittent spontaneous firing during the tourniquet inflation period. Receptive field size increased in five of five NR neurons with RF located proximal to the tourniquet cuff from 29 ± 10 mm 2 to 54 ± 30 mm 2 (RF area 1.9 ± 0.7; t = 2.7, P = .03). All five of these NR neurons also demonstrated an increase in spontaneous activity at 37 ± 14 minutes of tourniquet inflation which continued throughout the remainder of the tourniquet inflation period ( P < .05). Conclusions. The results of this study indicate that nerve compression and ischemia results in block of input to LTM neurons having RFs distal to the tourniquet cuff and an increase in spontaneous activity and expansion of the RFs of NRs, especially those with RFs located proximal to the tourniquet. Increases in spontaneous firing activity and expansion of the RFs of nociresponsive dorsal horn neurons receiving input from primary afferent nociceptors proximal to the tourniquet may explain, in part, the neurophysiologic mechanism of tourniquet-related pain.

Long-term alterations in opiate antinociception resulting from infant fentanyl tolerance and dependence

Postnatal day-14 (P14) infant rats remained naive or were implanted with osmotic minipumps infusing saline or fentanyl (50 μg kg −1 h −1). Fentanyl was administered 72 h later for measurement of antinociception in the tail-flick test. The potency of fentanyl was 3.0-fold lower in fentanyl-infused compared to saline-infused P17 rats. Fentanyl-infused P17 rats injected with naloxone underwent withdrawal characterized by increases in spontaneous activity, wall climbing, diarrhea, abdominal stretching, forepaw treading/tremors, wet-dog shakes, jumping, ptosis, rhinorrhea and hypothermia. Other naive, saline-infused and fentanyl-infused P17 rats not challenged with fentanyl or naloxone were housed until maturing into P42 juveniles. Fentanyl's potency was equal among each treatment group. However, morphine's potency was reduced in juveniles tolerant to fentanyl as infants. Morphine was also less potent in P90 adults tolerant to fentanyl as infants. Thus, chronic opiate exposure during infancy may affect the developing central nervous system, and desensitize animals and humans to opiate analgesia throughout life.