Response characteristics of specific thermoreceptive afferents innervating monkey facial skin and their relationship to human thermal sensitivity

The responses of thermoreceptive afferents to steady-state constant skin temperatures and temperature shifts were studied in rhesus monkeys by recording single fiber activity from fine dissected strands of the infraorbital nerve. Eighty-five warm and 134 cold fibers were identified by their specific sensitivity to warming and cooling of their receptive fields, which usually were restricted to single spots less than 1 mm in diameter. Warm fibers increased their firing rates with warming and decreased or ceased firing with cooling, while cold fibers showed an opposite behavior. Mean conduction velocity was 3.4 ± 1.7 m/s in warm fibers, and 9.0 ± 3.4 m/s in cold fibers.In response to constant skin temperatures in the innocuous temperature range below 43°C, warm fibers were active over the range of 30–42°C and showed maximum firing rates at 42°C. On the other hand, cold fibers were responsive to constant temperatures over the range of 20–42°C and their firing frequencies were maximal at 30°C and decreased as steady-state temperatures were raised or lowered. In addition, cold fibers exhibited periodic bursting activity when the temperature was below 35°C. The number of intraburst spikes in each burst increased as the constant temperature was     

Intrathecal apamin selectively facilitates activity in ascending axons of rat spinal cord evoked by stimulation of afferent C fibers in sural nerve

Intrathecally administered apamin was tested for its effect on activity in ascending axons of the spinal cord using decerebrate rats with low spinal cord transection. Afferent Aβ, Aδ or C fibers were stimulated in the sural nerve, and the response evoked in ascending axons was recorded below the transection. Apamin (5 ng) produced an increase in C fiber-evoked activity which developed about 30 min after injection and persisted for more than 60 min after injection. Apamin (5, 20 and 50 ng) did not change the activity in ascending axons which responded only to stimulation of afferent Aβ and Aδ fibers.The results indicate that apamin facilitates synaptic transmission from high-threshold afferent C fibers to secondary neurons.     

Organizing Effects of Rapsyn on Neuronal Nicotinic Acetylcholine Receptors

Targeting receptors to appropriate locations on the cell surface is a critical task for neurons. We have examined the possibility that rapsyn controls the distribution of nicotinic receptors on neurons as it does nicotinic receptors on muscle fibers. Cotransfection of QT6 cells with rapsyn and neuronal nicotinic receptor cDNA constructs produced receptor aggregates or clusters that codistributed in part with rapsyn protein. Though all nicotinic receptor subtypes tested were affected by rapsyn, receptors containing the α7 gene product were among the most responsive. In addition, rapsyn caused a portion of the nicotinic receptors containing α7 subunits to become resistant to solubilization with nonionic detergent and to display a marked increase in metabolic stability. The results are consistent with rapsyn linking the receptors to cytoskeletal elements and suggest that it may play an organizing role determining the fate and location of nicotinic receptors on neurons.     

The rostral projection of small diameter primary afferents in Lissauer's tract

The rostral projection of Aδ and C primary afferents in Lissauer's tract (LT) was studied by assessing how far, rostrally, axons entering at a given level could be activated by electrical stimulation. Sural Aδ primary afferents in LT exhibited a rostral projection at least as far as the L₃/L₄ border, 4 segments rostral to their segment of entry (S₁ dorsal root). C-fibers from the sural nerve projected in LT less than 2 segments rostral to their segment of entry. It is concluded that small afferent fibers can project appreciable distances along the spinal cord to bring them into regions not normally responsive to natural stimulation of the receptive field of such fibers.     

Deep innervation of sural nerve

Discharges of 37 sural afferents in the Aα to C fiber range have been recorded during stimulation of subcutaneous tissues after removal of the skin. Except for one Aα unit with muscle spindle properties, fibers were not easily excited by muscle stretching. The more slowly conducting fibers tended to have higher thresholds. After repeated stimulation, most Aδ and C units displayed a persistent afterdischarge which lasted from several minutes to more than half an hour.     

Sympathetic sprouting reverses decreases in membrane-associated activity of protein kinase C following septohippocampal denervation of the rat hippocampus

Hippocampal sympathetic ingrowth (HSI), a form of neuronal plasticity, is induced by medial septal lesions and consists of the sprouting of peripheral sympathetic fibers, arising from the superior cervical ganglion, into the dentate gyrus and CA₃ region of the hippocampus. HSI has been previously shown to alter learned and spontaneous behaviors, phosphatidyl inositide hydrolysis, and the antagonist binding kinetics of both muscarinic cholinergic receptors and phorbol ester receptors. We now report that sympathetic sprouting reverses decreases in membrane-associated activity of protein kinase C (PKC) following septohippocampal denervation of the rat hippocampus. Further, no changes were found in α, β or γ PKC isoenzymes among experimental groups, suggesting that the group A PKC isoforms do not mediate the observed changes in activity and phorbol ester binding.     

The Molecular and Cellular Basis of Cold Sensation

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Outflow of endogenous aspartate and glutamate from the rat spinal dorsal horn in vitro by activation of low- and high-threshold primary afferent fibers. Modulation by μ-opioids

Possible correlation of release of endogenous glutamate (Glu) and aspartate (Asp) with stimulation parameters used to activate primary sensory neurons was examined using the rat spinal cord slice — dorsal root ganglion preparation and high performance liquid chromatography with fluorimetric detection. Selective activation of the low-threshold (Aβ) primary afferent fibers resulted in a two-fold increase in the rate of basal outflow of Asp and a smaller increase in the outflow of Glu from the rat spinal dorsal horn slices into the superfusing medium. The activation of both the low (Aβ)- and the high-threshold (Aδ+C) primary afferents elicited also a significant increase in the outflow of Asp and Glu relative to control. Glu and Asp are released in significant amounts following superfusion of the dorsal root ganglia with capsaicin or resiniferatoxin. DAGO (Tyr-d-Ala-Gly-MePhe-Gly-ol-enkephalin), an agonist atμ-opioid receptors, attenuated the high-intensity stimulation-evoked outflow of Asp and Glu in a naloxone-sensitive manner. Our results have provided further evidence in support of the contention that Glu and Asp act as excitatory synaptic transmitters in the spinal dorsal horn. A role for μ-opioid receptors in modulation of spinal processing of somatosensory information is indicated.     

Effects of morphine and morphine withdrawal on adrenergic neurons of the rat rostral ventrolateral medulla

In urethane anesthetized rats, iontophoretic application of morphine or α-methylnoradrenaline (α-MNE) inhibited (80–100%) the discharges of all putative adrenergic (C1) cells of the rostral ventrolateral medulla (RVLM). The effect of morphine was blocked selectively by naloxone while that of α-MNE was blocked selectively by theα₂-adrenergic antagonist idazoxan. Putative C1 cells were inhibited (75–100%) by low i.v. doses of clonidine (10–15 μg/kg). Most cells (7/10) were also inhibited by morphine i.v. (81% at 7 mg/kg). Two cells were slightly excited at doses below 2 mg/kg and inhibited at higher doses. Three cells were excited only. All effects of morphine i.v. were reversed by naloxone (1 mg/kg, i.v.). Intravenous administration of naloxone to morphine-dependent rats increased significantly the firing rate of all putative C1 adrenergic cells (from 5.8 ± 0.9 spikes/s to 12.3 ± 1.5 spikes/s;n = 8). During withdrawal these cells could still be inhibited (80–100%) by i.v. injection of clonidine (15 μg/kg). C-Fos expression induced by naltrexone-precipitated withdrawal was examined in the brainstem of freely moving morphine-dependent rats pretreated with clonidine or saline before injection of the opioid antagonist. The locus coeruleus (LC) of the same rats was examined for comparison. Morphine withdrawal without clonidine treatment significantly increased the number of Fos-like-immunoreactive (Fos-LIR) cells in the RVLM and LC. Clonidine pretreatment (1 mg/kg, i.p.) reduced the number of withdrawal-activated Fos-LIR cells in LC by 81%. In the RVLM this reduction averaged 37% for all cell types and 48% for C1 adrenregic cells. Further, a very large proportion of RVLM neurons that expressed c-Fos during morphine withdrawal (83%) were immunoreactive forα₂A-adrenergic receptors. This study suggests that, like noradrenergic cells of the LC, C1 adrenergic neurons of the RVLM are: (i) inhibited by both opiate andα₂-adrenergic receptor agonists; and (ii) activated during naloxone-precipitated morphine withdrawal, Since C1 cells are considered essential to sympathetic tone generation, their inhibition by morphine may contribute to the hypotensive effects of this opioid agonist in non-dependent individuals. Their excitation during opiate withdrawal may also contribute to the autonomic activation that characterizes this syndrome. Finally, inhibition of C1 cells by clonidine may contribute to the clinically recognized efficacy of this drug to attenuate autonomic signs of opiate withdrawal.     

Reduced thermal sensitivity in the rabbit by β-endorphin injection into the preoptic/anterior hypothalamus

Male New Zealand White rabbits,Oryctolagus cuniculus, were stereotaxically implanted with a guide tube above the preoptic/anterior hypothalamus (PO/AH) for the injection of β-endorphin (β-E) or saline at ambient temperatures of 20 and 25 °C. Ear skin and PO/AH temperatures were recorded in loosely restrained control and β-E-pretreated rabbits while radiant heat was applied to the dorsal skin. Without β-E administration the ear skin temperature (T_ear) underwent a rapid increase during back heating. Following β-E administration there was a marked vasoconstriction along with a large reduction in responsiveness of ear skin temperature to radiant 3eat. The time to respond to radiant heat for β-E-pretreated rabbits was significantly longer than that for control rabbits. In control animals, the increase in T_ear in response to radiant heat exposure dependend upon the initial ear temperatures. However, in β-E-pretreated rabbits vasodilatation response to radiant heat exposure was nearly the same regardless of the initial T_ear. These data suggest that there is a significant reduction in passage of temperature information from cutaneous thermal receptors to the PO/AH in β-E-pretreated animals and that β-E-induced reduction in sensitivity of the vasomotor system to radiant heat may account for the effectiveness of this opioid peptide to promote hyperthermia in the rabbit.     

Thermoresponsiveness of posterior hypothalamic (PH) neurons of rats to scrotal and abdominal thermal stimulation

The thermoresponsiveness of posterior hypothalamic (PH) neurons to localized, incremental thermal heating and cooling between 10–40°C of the abdomen or scrotum was determined in urethane anesthetized, male Sprague–Dawley rats whose core temperature was maintained at 37°C during testing. PH extracellular neuronal activity was recorded along with changes in gastrocnemius muscle EMG activity and temperature (T_ms, indicative of shivering thermogenesis) and intrascapular brown adipose tissue temperature (T_IBATs, indicative of non-shivering thermogenesis). Seventy-five PH neurons were recorded following both scrotal and abdominal trials of thermal stimulation. Nine percent of PH neurons were classified as warm responsive neurons (WRNs), 20% as cold responsive (CRNs), and 71% as temperature nonresponsive neurons (TNRNs), based on their thermal coefficients (TCs). Mean TC for warm PH neurons was significantly increased with scrotal warming between 30–40°C from the mean TC of the same PH WRNs following abdominal warming. Similarly, the thermal coefficient was increased (i.e., was more negative) for cold responsive PH neurons to scrotal cooling (20–10°C) as opposed to the TC of the same PH CRNs for abdominal cooling. No shivering thermogenesis (no change in temperature or EMG activity from gastrocnemius muscle) or non-shivering thermogenesis (no significant increase in IBAT temperatures) occurred with scrotal or abdominal cooling in these 21°C acclimatized rats. The results indicate that a small population of PH neurons are thermoresponsive to localized physiological changes in temperature of the scrotum and abdomen with greater thermoresponsiveness shown of both warm and cold PH neurons to scrotal vs. abdominal thermal stimulation.     

Streptozotocin-induced diabetes selectively alters the potency of analgesia produced by μ-opioid agonists, but not by δ- and κ-opioid agonists

To investigate the possible mechanisms of the alterations in morphine-induced analgesia observed in diabetic mice, we examined the influence of streptozotocin-induced (STZ-induced) diabetes on analgesia mediated by the different opioid receptors. The antinociceptive potency of morphine (10 mg/kg), administered s.c., as determined by both the tail-pinch and the tail-flick test, was significantly reduced in diabetic mice as compared to that in controls. Mice with STZ-induced diabetes had significantly decreased sensitivity to intracerebroventricularly (i.c.v.) administered μ-opioid agonists, such as morphine (10 μg) and [d-Ala², N-Me Phe⁴,Gly-ol⁵]enkephalin (DAMGO, 0.5 μg). However, i.c.v. administration of [d-Pen^2,5]enkephalin (DPDPE, 5 μg), a δ-opioid agonist, and U-50,488H (50 μg), a κ-opioid agonist, produced pronounced antinociception in both control and diabetic mice. Furthermore, there were no significant differences in antinociceptive potency between diabetic and control mice when morphine (1 μg), DAMGO (10 μg), DPDPE (0.5 μg) or U-50,488H (50 μg) was administered intrathecally. In conclusion, mice with STZ-induced diabetes are selectively hyporesponsive to supraspinal μ-opioid receptor-mediated antinociception, but they are normally responsive to activation of δ- and κ-opioid receptors.     

Effect of climatic temperature on the age of onset of Huntington's chorea

The age of 1,403 subjects at onset of Huntington's chorea were drawn from the literature and related to the mean annual, January, and July temperatures of their place of residence. When the data were converted into mean annual, winter, and summer isotherms covering a range of 10° F (5·6° C), there was a statistically significant decrease in age of onset as the temperature increased. Over the ranges studied, winter temperatures exerted a stronger effect than summer temperatures. To reduce interference by ethnic factors, the analysis was repeated on North American subjects with similar results. It is suggested that repeated infections may provoke chorea and that the observed lowering of the age of onset is associated with increased susceptibility to infection on passing from cold to warm climates.     

Immunohistochemical localization of a neuron-specific β-tubulin isotype in the developing chicken ultimobranchial glands

The localization of a neuron-specific β-tubulin isotype in the ultimobranchial glands from chickens at various stages of development was studied by means of light- and electron microscopic immunohistochemistry with a monoclonal antibody (TuJ1) against the β-tubulin isotype, cβ4. At 8 days of incubation, many C cells in the ultimobranchial glands showed immunoreactivity for TuJ1 in variable degrees, weak to intense. At 12 days of incubation, a vast majority of C cells were intensely immunoreactive for TuJ1, and further TuJ1-immunoreactive nerve fibers were distributed in the ultimobranchial glands. At 14 and 16 days of incubation, intense immunoreactivity for TuJ1 was sustained in the C cells. Electron microscopic analyses revealed that TuJ1 immunoreactivity was diffusely distributed throughout the cytoplasm and also localized on the secretory granules of C cells at these stages. TuJ1 immunoreactivity in the C cells started to decrease at late stages of embryonic development. At the hatching period, dense distributions of TuJ1-immunoreactive nerve fibers were observed in the ultimobranchial glands, whereas TuJ1 immunoreactivity of the C cells became very weak. In 10-day-old chickens, TuJ1 immunoreactivity was restricted to the nerve fibers.     

Prenatal exposure to morphine differentially alters gonadal hormone regulation of δ-opioid receptor binding in male and female rats

The present study tested the hypothesis that exposure to morphine on gestation days 11–18 differentially alters δ-opioid receptors in the brain of adult male and female rats. In Experiment 1, the binding characteristics of δ-opioid receptors were examined in membrane homogenates from six brain regions, including the hypothalamus (HYP), preoptic area, frontal cortex (CX), ventral tegmental area, striatum (STR) and cerebellum of adult male and female rats. In Experiment 2, the density of δ-opioid receptors was assessed in the CX and STR using receptor autoradiography. Prenatal morphine exposure has no effects on δ-opioid receptors in the brain of gonadally intact, adult male rats regardless of methodology. However, when male rats were gonadectomized in Experiment 2, morphine-exposed males have fewer δ-opioid receptors than controls in the CX but not in the STR. These reductions in cortical δ-opioid receptors are restored by testosterone replacement, demonstrating that prenatal morphine exposure alters testosterone regulation in the CX of male rats. In ovariectomized (OVX) female rats, prenatal morphine exposure increases the density of δ-opioid receptors in the frontal CX. Interestingly, this up-regulation of δ-opioid receptors is not present when the CX is investigated by autoradiography. Moreover, progesterone given alone or in combination with estrogen reduces the density of δ-opioid receptors in the CX and STR of both saline- and morphine-exposed, OVX females. Thus, mid to late gestational morphine exposure differentially alters the influence of adult gonadal hormones on δ-opioid receptors in the CX, decreasing the sensitivity in females and increasing it in males. This is also the first report to demonstrate that gonadal hormones regulate δ receptor densities in brain regions other than the HYP of OVX females.     

Analysis of facial cold receptor activity in the rat

Afferent activity of single facial cold receptors was extracellularly recorded from infraorbital nerve fibers in the rat, and the response properties of 28 receptors to thermal stimulation were quantitatively studied. Generally, on repeated stimulation, the afferent activity was highly reproducible and was not dependent on previous adapting temperatures. At constant temperatures, a periodic pattern was apparent in the discharges of 24 receptors; in the remaining 4 receptors periodic elements could not reliably be detected. The temperature dependence of the cyclic pattern corresponded to that observed in other mammalian cold receptor populations: we observed regular impulse groups (bursts) at lower and beating activity at higher adapting temperatures. Rapid changes of temperature induced transient alterations of activity. The dynamic response to cooling was biphasic, indicating a complex sequence of receptor events. A transient acceleration of impulse frequency was followed by a dynamic burst discharge which was characterized by longer pauses and a greater number of impulses per burst compared with the steady-state activity at the same temperature. This indicates a deceleration of the periodic receptor events during the adaptation process following dynamic responses, which is accompanied by a concomitant shift of these processes to a more pronounced suprathreshold condition. In an additional series of experiments, parameters of the periodic activity in the rat were compared with corresponding data of facial and lingual cold receptors in the cat. Whereas the number of impulses per cycle was similar in the 3 receptor populations, the frequency of the periodic pattern proved to be considerably higher in the rat than in the cat.     

The Influence of a Targeted Deletion of the IFNγ Gene on Emotional Behaviors

Evidence suggests that interferon-gamma (IFNγ) plays an important role in CNS function and development. While the paucity of agents that selectively modify IFNγ production or interaction with its receptors makes analyses of its potential behavioral relevance difficult, mice with null mutations of the IFNγ gene have been used to investigate the potential role of IFNγ in emotional behaviors. C57Bl/6 (B6) mice with null mutations of the IFNγ gene (IFNγ (−/−)) showed significantly increased emotionality compared to the wild-type (IFNγ (+/+)) B6 mice. This was manifested in performance in the elevated plus maze as well as increased defecation scores and decreased locomotor activity both in novel environments and following a sonic stimulus. In contrast, the general level of emotionality of both IFNγ (+/+) and (−/−) BALB/c (C) mice was substantially greater than that of either of the B6 mouse groups. While C IFNγ (−/−) showed increased immobility in response to novelty, other indices of emotionality of C IFNγ (−/−) mice were not significantly different from those of the C IFNγ (+/+) mice. In summary, the lack of IFNγ appears to contribute to increased emotionality, but the basal behaviors of the parental strain (e.g., BALBc) may overshadow the expression of this emotionality. While mice with null mutations of the IFNγ gene may be useful tools for investigating the role of IFNγ in brain function and behavior, the influence of the parent strain genome(s) on the behaviors in question must be taken into account.     

Thermoreceptors and thermosensitive afferents

Cutaneous thermosensation plays an important role in thermal regulation and detection of potentially harmful thermal stimuli. Multiple classes of primary afferents are responsive to thermal stimuli. Afferent nerve fibers mediating the sensation of non-painful warmth or cold seem adapted to convey thermal information over a particular temperature range. In contrast, nociceptive afferents are often activated by both, painful cold and heat stimuli. The transduction mechanisms engaged by thermal stimuli have only recently been discovered. Transient receptor potential (TRP) ion channels that can be activated by temperatures over specific ranges potentially provide the molecular basis for thermosensation. However, non-TRP mechanisms are also likely to contribute to the transduction of thermal stimuli. This review summarizes findings regarding the transduction proteins and the primary afferents activated by innocuous and noxious cold and heat.     

Characterization of nicotinic receptors in immortalized hippocampal neurons

Nicotinic acetylcholine receptors, particularly nicotinic a-bungarotoxin (a-BGT) receptors, are present in relatively high concentrations in rat hippocampus. Because of the difficulties encountered in studying receptors using primary cells in culture, especially for biochemical work, we investigated the possibility of using an immortalized cell line from embryonic rat hippocampus (H19-7). RNase protection assays show that α4, α7 and β2 neuronal nicotinic receptor subunit mRNAs are present in differentiated but not undifferentiated H19-7 cells, while α2, α3, α5 and β3 subunit mRNAs were not detectable under either condition. In line with these results, the present data demonstrate that the H19-7 cells express cell surface nicotinic a-BGT binding sites, which were maximal after seven days of differentiation in culture. The receptors were saturable, of high affinity (K_d = 1.30 nM and B_max = 11.70 fmol/10⁵ cells) and had a pharmacological profile similar to that observed for CNS a-BGT receptors. On the other hand, although α4 and β2 neuronal nicotinic subunit mRNAs were present in differentiated H19-7 cells, no [3H]cytisine binding was observed. Because immortalized cell lines have the advantage that they provide a limitless supply of cells as compared to primary cell cultures, but yet are not malignant in origin, the present results may suggest that the H19-7 immortalized hippocampul cell line represent a useful CNS model system for examining α-BGT nicotinic receptors.