Modulation of Multisensory Nociceptive Neurons In Monkey Cortical Area 7b.

Wide range thermoreceptive neurons (WRT-EN) in monkey cortical area 7b that encoded innocuous and nocuous cutaneous thermal and threatening visuosensory stimulation with high fidelity were studied to identify their multisensory integrative response properties. Emphasis was given to characterizing the spatial and temporal effects of threatening visuosensory input on the thermal stimulus-response properties of these multisensory nociceptive neurons. Threatening visuosensory stimulation was most efficacious in modulating thermal evoked responses when presented as a downward ("looming"), spatially congruent, approaching and closely proximal target in relation to the somatosensory receptive field. Both temporal alignment and misalignment of spatially aligned threatening visual and thermal stimulation significantly increased mean discharge frequencies above those evoked by thermal stimulation alone, particularly at near noxious (43°C) and mildly noxious (45°C) temperatures. The enhanced multisensory discharge frequencies were equivalent to the discharge frequency evoked by overtly noxious thermal stimulation alone at 47°C (monkey pain tolerance threshold). A significant increase in behavioral mean escape frequency with shorter escape latency was evoked by multisensory stimulation at near noxious temperature (43°C ) which was equivalent to that evoked by noxious stimulation alone (47°C).The remarkable concordance of elevating both neural discharge and escape frequency from a non-nociceptive and pre-pain level by near noxious thermal stimulation to a nociceptive and pain level by multisensory visual and near noxious thermal stimulation and integration is an elegantly designed defensive neural mechanism that in effect lowers both nociceptive response and pain thresholds to preemptively engage nocifensive behavior and consequently, avert impending and actual injurious noxious thermal stimulation.

Vibration perception thresholds of human vital and nonvital maxillary incisors.

OBJECTIVE: Vibrations applied to human teeth have been shown to induce vibrotactile sensations although the location of the mechanoreceptors responsible for encoding vibrations is unclear. The aim of this study is to test the hypothesis that vibrotactile tooth sensations depend on afferent input from intradental mechanoreceptors. DESIGN: Vibration perception thresholds were determined for a vital (control) and a contralateral nonvital (endodontically treated) maxillary incisor in 11 healthy human participants using an adaptive psychophysical procedure. An electromechanical vibrator was used to deliver sinusoidal vibrations at 10 frequencies between 40 and 315 Hz. RESULTS: The median force thresholds ranged between 41 and 215 mN for vital and 71 and 507 mN for nonvital incisors. Nonvital median force thresholds were significantly higher than vital thresholds at all frequencies between 40 and 315 Hz. A linear regression analysis revealed a significant increase in vibrotactile thresholds with increasing frequency for only the vital incisors. CONCLUSIONS: The results support the hypothesis that mechanoreceptors located within the tooth contribute to vibrotactile tooth sensations and that mechanosensory information from both periodontal ligament and intradental mechanoreceptors facilitates the accurate assessment of food textures during mastication.

Binge-like postnatal alcohol exposure triggers cortical gliogenesis in adolescent rats.

The long-term effects of binge-like postnatal alcohol exposure on cell proliferation and differentiation in the adolescent rat neocortex were examined. Unlike the hippocampal dentate gyrus, where proliferation of progenitors results primarily in addition of granule cells in adulthood, the vast majority of newly generated cells in the intact mature rodent neocortex appear to be glial cells. The current study examined cytogenesis in the motor cortex of adolescent and adult rats that were exposed to 5.25 g/kg/day of alcohol on postnatal days (PD) 4-9 in a binge manner. Cytogenesis was examined at PD50 (through bromodeoxyuridine [BrdU] labeling) and survival of these newly generated cells was evaluated at PD80. At PD50, significantly more BrdU-positive cells were present in the motor cortex of alcohol-exposed rats than controls. Confocal analysis revealed that the majority (>60%) of these labeled cells also expressed NG2 chondroitin sulfate proteoglycan (NG2 glia). Additionally, survival of these newly generated cortical cells was affected by neonatal alcohol exposure, based on the greater reduction in the number of BrdU-labeled cells from PD50 to PD80 in the alcohol-exposed animals compared to controls. These findings demonstrate that neonatal alcohol exposure triggers an increase in gliogenesis in the adult motor cortex.

Persistent impairment of hippocampal neurogenesis in young adult rats following early postnatal alcohol exposure.

BACKGROUND: Prenatal alcohol exposure can cause damage to the developing fetus with outcomes including growth deficiency, facial dysmorphology, brain damage, and cognitive and behavioral deficits. Smaller brains in children with FASD have been linked both with reduced cell proliferation in the developing CNS and with apoptotic cell loss of postmitotic neurons. Prenatal alcohol exposure in rodents during the period of brain development comparable to that of the first and second trimesters of human pregnancy persistently alters adult neurogenesis. Long-term effects of alcohol exposure during the third trimester equivalent, which occurs postnatally in the rat, on adult neurogenesis have not been previously reported. The goal of this study was to examine the effect of postnatal binge-like alcohol exposure on cell proliferation and neurogenesis in hippocampal dentate gyrus during adolescence and young adulthood. METHODS: Male Long-Evans rat pups were assigned to 3 groups: alcohol-exposed (AE), sham-intubated (SI) or suckle control (SC). AE pups received ethanol in a milk formula in a binge manner (2 feedings, 2 hours apart, total dose 5.25 g/kg/day) on postnatal days (PD) 4-9. BrdU was injected every other day on PD30-50. Animals were perfused either on PD50 to examine cytogenesis and neurogenesis in hippocampal dentate gyrus at the end of BrdU injections or on PD80 to evaluate new cell survival. Dorsal hippocampal sections were immunostained for BrdU, a marker for proliferating cells, Ki67, endogenous marker of proliferation, and NeuN, a marker for mature neurons. RESULTS: Binge-like alcohol exposure on PD4-9 significantly reduced the number of mature neurons in adult hippocampal dentate gyrus (DG) both on PD50 and PD80, without altering cumulative cytogenesis on PD50. In addition, the number of new neurons, that were generated between PD30 and 50, was further reduced after 30 days of survival in all 3 groups (SC, SI, and AE). CONCLUSIONS: These observations suggest that early postnatal binge alcohol exposure results in long-term deficits of adult hippocampal neurogenesis, providing a potential basis for the deficits of hippocampus-dependent behaviors reported for this model.

Fragile X mental retardation protein shifts between polyribosomes and stress granules after neuronal injury by arsenite stress or in vivo hippocampal electrode insertion.

Fragile X mental retardation protein (FMRP), the lack of which causes fragile X syndrome, is an RNA-binding protein encoded by the FMR1 gene. FMRP accompanies mRNAs from the nucleus to dendritic regions and is thought to regulate their translation at synapses. It has been shown that FMRP moves into nontranslating stress granules (SGs) during heat stress of cultured fibroblasts (Mazroui et al., 2002). We used a novel method to isolate SGs from neurons by virtue of their TIA-1 (T-cell intracellular antigen 1) protein component, and found that FMRP moved out of polyribosomes and into SGs subsequent to oxidative stress. We then examined FMRP changes in subcellular localization resulting from mechanically induced neuronal injury by placement of electrodes into the dentate gyrus and the perforant path of the hippocampus in vivo. During the first 10 min after electrode insertion into one hippocampus, FMRP shifted into SGs and away from polyribosomes, in both hippocampi. Although the injury discharge subsided beyond 10 s, FMRP levels in polyribosomes and stress granules did not return to basal levels until 30 min after electrode penetration. Our findings suggest that procedures for in vivo induction of long-term potentiation or long-term depression should incorporate a 30 min rest period after electrode insertion, and indicate that the contralateral hippocampus cannot be considered an unstimulated control tissue.

Mandatory " enriched" housing of laboratory animals: the need for evidence-based evaluation.

Environmental enrichment for laboratory animals has come to be viewed as a potential method for improving animal well-being in addition to its original sense as a paradigm for learning how experience molds the brain. It is suggested that the term housing supplementation better describes the wide range of alterations to laboratory animal housing that has been proposed or investigated. Changes in the environments of animals have important effects on brain structure, physiology, and behavior--including recovery from illness and injury--and on which genes are expressed in various organs. Studies are reviewed that show how the brain and other organs respond to environmental change. These data warrant caution that minor cage supplementation intended for improvement of animal well-being may alter important aspects of an animal's physiology and development in a manner not easily predicted from available research. Thus, various forms of housing supplementation, although utilized or even preferred by the animals, may not enhance laboratory animal well-being and may be detrimental to the research for which the laboratory animals are used.

Plasticity of nonneuronal brain tissue: roles in developmental disorders.

Neuronal and nonneuronal plasticity are both affected by environmental and experiential factors. Remodeling of existing neurons induced by such factors has been observed throughout the brain, and includes alterations in dendritic field dimensions, synaptogenesis, and synaptic morphology. The brain loci affected by these plastic neuronal changes are dependent on the type of experience and learning. Increased neurogenesis in the hippocampal dentate gyrus is a well-documented response to environmental complexity ("enrichment") and learning. Exposure to challenging experiences and learning opportunities also alters existing glial cells (i.e., astrocytes and oligodendrocytes), and up-regulates gliogenesis, in the cerebral cortex and cerebellum. Such glial plasticity often parallels neuronal remodeling in both time and place, and this enhanced morphological synergism may be important for optimizing the functional interaction between glial cells and neurons. Aberrant structural plasticity of nonneuronal elements is a contributing factor, as is aberrant neuron plasticity, to neurological and developmental disorders such as epilepsy, autism, and mental retardation (i.e., fragile X syndrome). Some of these nonneuronal pathologies include abnormal cerebral and cerebellar white matter and myelin-related proteins in autism; abnormal myelin basic protein in fragile X syndrome (FXS); and abnormal astrocytes in autism, FXS, and epilepsy. A number of recent studies demonstrate the possibility of using environmental and experiential intervention to reduce or ameliorate some of the neuronal and nonneuronal abnormalities, as well as behavioral deficits, present in these neurological and developmental disorders.

The role of the basal ganglia in nociception and pain.

The involvement of the basal ganglia in motor functions has been well studied. Recent neurophysiological, clinical and behavioral experiments indicate that the basal ganglia also process non-noxious and noxious somatosensory information. However, the functional significance of somatosensory information processing within the basal ganglia is not well understood. This review explores the role of the striatum, globus pallidus and substantia nigra in nociceptive sensorimotor integration and suggests several roles of these basal ganglia structures in nociception and pain. Electrophysiological experiments have detailed the non-nociceptive and nociceptive response properties of basal ganglia neurons. Most studies agree that some neurons within the basal ganglia encode stimulus intensity. However, these neurons do not appear to encode stimulus location since the receptive fields of these cells are large. Many basal ganglia neurons responsive to somatosensory stimulation are activated exclusively or differentially by noxious stimulation. Indirect techniques used to measure neuronal activity (i.e., positron emission tomography and 2-deoxyglucose methods) also indicate that the basal ganglia are activated differentially by noxious stimulation. Neuroanatomical experiments suggest several pathways by which nociceptive information may reach the basal ganglia. Neuroanatomical studies have also indicated that the basal ganglia are rich in many different neuroactive chemicals that may be involved in the modulation of nociceptive information. Microinjection of opiates, dopamine and gamma-aminobutyric acid (GABA) into the basal ganglia have varied effects on pain behavior. Administration of these neurochemicals into the basal ganglia affects supraspinal pain behaviors more consistently than spinal reflexive behaviors. The reduction of pain behavior following electrical stimulation of the substantia nigra and caudate nucleus provides additional evidence for a role of the basal ganglia in pain modulation. Some patients with basal ganglia disease (e.g., Parkinson's disease, Huntington's disease) have alterations in pain sensation in addition to motor abnormalities. Frequently, these patients have intermittent pain that is difficult to localize. Collectively, these data suggest that the basal ganglia may be involved in the (1) sensory-discriminative dimension of pain, (2) affective dimension of pain, (3) cognitive dimension of pain, (4) modulation of nociceptive information and (5) sensory gating of nociceptive information to higher motor areas. Further experiments that correlate neuronal discharge activity with stimulus intensity and escape behavior in operantly conditioned animals are necessary to fully understand how the basal ganglia are involved in nociceptive sensorimotor integration.

The effect of thalamic nucleus submedius lesions on nociceptive responding in rats.

Previous studies have shown that the thalamic nucleus submedius (SM) contains nociceptive neurons and is interconnected with spinal, brain-stem and cortical regions associated with nociception. The present study was performed to examine the role of the SM in nociceptive-related behaviors. The effect of SM lesions on nociceptive responding in rats was assessed using both the radiant-heat tail-flick (TF) and the tail-shock 'pain-induced' vocalization (PIV) tests. The results of Exp. 1 indicated that the intensity of electrical shock required for vocalization responses was significantly decreased following SM lesions. No changes in vocalization responses were present in the sham-lesion group. In contrast, both the sham- and SM-lesion groups exhibited a significant post-lesion increase in TF latencies. A second experiment was performed to determine whether the effects of SM lesion on the tail flick may have been masked by conditioned antinociception associated with noxious electrical stimulation of the tail to produce PIV. The results indicated that there was no post-lesion change in TF latencies in either the SM- or sham-lesion group when the antecedent PIV test was omitted. The results suggest that the SM may play a role in supraspinally mediated inhibition of nociceptive input but not in spinally mediated responses to noxious stimuli.

D-phenylalanine: a putative enkephalinase inhibitor studied in a primate acute pain model.

D-Phenylalanine, along with morphine, acetylsalicylic acid and zomepirac sodium were evaluated for their antinociceptive actions in monkeys (M. fascicularis) trained to autoregulate nociceptive stimulation using a discrete-trials, aversive-threshold paradigm. Morphine sulfate produced dose-related increases in aversive threshold which were reversible after administration of naloxone (12.5 or 25 micrograms/kg i.m.). D-Phenylalanine (500 mg/kg p.o.) produced a small increase in aversive threshold which was not statistically significant and not naloxone reversible. Acetylsalicylic acid (200 mg/kg p.o.) but not zomepirac sodium (200 mg/kg p.o.) in combination with D-phenylalanine (500 mg/kg) produced a small statistically significant increase in aversive threshold. Our results argue against the hypothesis that D-phenylalanine is responsible for increasing aversive thresholds via opiate receptor mechanisms involving increased activity of enkephalins at synaptic loci. Previous studies by others in rats and mice showed that D-phenylalanine and acetylsalicylic acid produced increases in nociceptive thresholds which were naloxone reversible. Our failure to find opiate receptor mediated analgesia in a primate model with demonstrated opiate receptor selectivity and sensitivity is discussed in terms of previous basic and clinical research indicating an analgesic role for D-phenylalanine. Possible species difference in drug action is discussed in terms of inhibition by D-phenylalanine of carboxy-peptidase-like enkephalin processing enzymes as well as inhibition of carboxypeptidase-like enkephalin degrading enzymes.

Tooth pulp-evoked potentials in the monkey: cortical surface and intracortical distribution.

The distribution of tooth pulp-evoked potentials (TPEPs) was characterized in the primary motor (MI), primary somatosensory (SI) and secondary somatosensory (SII) cortices of the monkey. Bipolar electrical tooth pulp stimulation elicited TPEP components P23 and N44 over SI, P26 and N72 over MI, and P72, N161, P280, N420, P561 and N662 over SII. Muscular artifacts and extradental input did not affect the TPEP as demonstrated by experiments using a neuromuscular blocking agent and removal of the pulp, respectively. The short latency TPEPs recorded over SI and MI were evoked by low stimulus intensities and activation of A beta nerve fibers, whereas the long latency TPEPs recorded over SII required higher stimulus intensities and the additional recruitment of A delta nerve fibers. Intracortical recordings revealed polarity reversals of components P23 and N44 in area 3b, P26 and N72 in area 4, and P72, N161, P280, N420, P561 and N662 in the upper bank of the lateral sulcus (SII). Evidence presented in this study suggests that TPEPs recorded from SI and MI relate to non-nociceptive mechanisms while TPEPs recorded from SII relate to nociceptive mechanisms.

Neuroma pain model: correlation of motor behavior and body weight with autotomy in rats.

A rat pain model was investigated by examining the correlation of autotomy (self-mutilation) score with motor behavior and body weight change after sciatic nerve transection, encapsulation and neuroma formation. Observations of motor behavior and body weight changes (e.g. feeding behavior) as an index of pain were considered to have several advantages over scoring the degree of autotomy. Motor activity of 14 rats (12 neuroma, 2 sham), measured using a stabilimeter, was compared on a weekly basis to autotomy scores for a total of 7 weeks after surgery. Additionally, body weight of 26 rats (20 neuroma, 6 sham surgery) was monitored for 4 weeks following surgery. While autotomy, changes in body weight and abnormalities in motor behavior were observed after surgery, no significant Spearman rank correlation coefficients were determined for any week and thus no significant relationships were found between autotomy score and motor activity or body weight. However, it was observed that rats after sham surgery gained significantly more weight than rats after sciatic nerve transection. Therefore, these results cast doubt on the validity of autotomy score as the sole index of pain.