Stimulation Of Receptive Field Research Articles

The effects of the TRPV1 receptor antagonist SB-705498 on trigeminovascular sensitisation and neurotransmission

This report examines the effect of the transient receptor potential vanilloid 1 receptor antagonist SB-705498 on neurotransmission and inflammation-induced sensitisation in the trigeminovascular sensory system. A single-neuron electrophysiological animal model for neurovascular head pain was used to evaluate dural and facial noxious inputs and the effects of SB-705498 administered by intravenous (i.v.) injection. Electrical and mechanical stimulation of the dura mater and the facial skin activated second-order neurons in the trigeminal nucleus caudalis of cats, with A-delta latencies. Intravenous injection of SB-705498 (2 mg kg(-1)) produced a slowly developing and long-lasting suppression of responses to dural and skin stimulation. Maximum suppression occurred by 1 h and reached 41% for dura and 24% for skin. Intravenous injection of drug vehicle did not produce significant suppression of responses to stimulation of either dura or skin. Intravenous injection of SB-705498 produced a brief and small rise in blood pressure and dural blood flow, which both returned to normal before suppression of the responses to stimulation became manifest. Application of "inflammatory soup" to the dura mater produced a pronounced increase in dural blood flow and induced a slowly developing increase in the responses of neurons to both electrical and mechanical stimulations of their facial and dural receptive fields. This sensitisation reached a maximum in 60-90 min, at which time responses had risen to approximately twice that of control levels seen before the application of inflammatory soup. Intravenous injection of SB-705498 subsequent to the development of sensitisation produced a slowly developing, prolonged and statistically significant reversal of the sensitisation induced by inflammatory soup. Maximum reversal of sensitisation to electrical stimulation occurred by 150-180 min, when responses had fallen to, or below, control levels. At 70-85 min following injection of SB-705498, the responses of previously sensitised neurons to mechanical stimulation of dura mater and facial receptive field had also returned to near control levels. SB-705498 was also able to prevent the development of sensitisation; application of inflammatory soup to the dura mater induced a slowly developing increase in the responses of neurons to electrical stimulation of the skin and dura mater in cats which had received an i.v. injection of vehicle for SB-705498 but not in cats which had received the active drug. Blood levels of SB-705498 were maximal immediately following i.v. injection and declined over the following 2 h. Significant brain levels of SB-705498 were maintained for up to 9 h. These results suggest that SB-705498 may be an effective suppressant and reversal agent of the sensitisation to sensory input which follows inflammation in the trigeminovascular sensory distribution but may not be particularly useful in blocking primary pain processes such as migraine headache. SB-705498 could thus potentially prevent, modify or reverse the cutaneous trigeminal allodynia seen in certain migraine conditions, especially "transformed" migraine.

Effect of electroacupuncture on thalamic neuronal response to visceral nociception

The thalamus has been shown to play an important role in somatovisceral integration. This study set out to examine thalamic neuronal responses to visceral nociception when electrical stimulation was applied to the skin receptive field (RF) or to ST 36, an acupoint most frequently used for abdominal pain conventionally. Single neuronal recordings were carried out extracellularly in the thalamic ventrobasal nucleus of anaesthetized rats. Among numerous neurons responding to tactile stimulation, 72 units were found responsive not only to innocuous stimulation on skin RF (60 activated, 12 inhibited) but also to noxious colorectal distension (CRD). Electrical stimulation (2 Hz, 1 mA) of the neuronal somatic receptive field center reduced the subsequent neuronal responses to CRD in 40 neurons tested. High frequency stimulation (100 Hz) produced stronger inhibition than low frequency (2 Hz) stimulation at RF. The inhibition on visceral nociceptive response occurred immediately after the stimulation. In comparison with the effect of RF stimulation, the inhibitory effect was less at either ipsilateral or contralateral ST 36. Our data suggest that, at single thalamic neuron level, stimulation at conventional acupoint is not necessarily as effective as stimulation at neuronal skin receptive field, and high frequency is more effective than low frequency stimulation for the inhibition of visceral nociception.

Characterization of Mouse Lumbar Splanchnic and Pelvic Nerve Urinary Bladder Mechanosensory Afferents

Sensory information from the urinary bladder is conveyed via lumbar splanchnic (LSN) and sacral pelvic (PN) nerves to the spinal cord. In the present report we compared the mechanosensitive properties of single afferent fibers in these two pathways using an in vitro mouse bladder preparation. Mechanosensitive primary afferents were recorded from the LSN or PN and distinguished based on their response to receptive field stimulation with different mechanical stimuli: probing (160 mg to 2 g), stretch (1-25 g), and stroking of the urothelium (10-1,000 mg). Four different classes of afferent were recorded from the LSN and PN: serosal, muscular, muscular/urothelial, and urothelial. The LSN contained principally serosal and muscular afferents (97% of the total sample), whereas all four afferent classes of afferent were present in the PN (63% of which were muscular afferents). In addition, the respective proportions and receptive field distributions differed between the two pathways. Both low- and high-threshold stretch-sensitive muscular afferents were present in both pathways, and muscular afferents in the PN were shown to sensitize after exposure to an inflammatory soup cocktail. The LSN and PN pathways contain different populations of mechanosensitive afferents capable of detecting a range of mechanical stimuli and individually tuned to detect the type, magnitude, and duration of the stimulus. This knowledge broadens our understanding of the potential roles these two pathways play in conveying mechanical information from the bladder to the spinal cord.

Local luminance and contrast in natural images

Within natural images there is substantial spatial variation in both local contrast and local luminance. Understanding the statistics of these variations is important for understanding the dynamics of receptive field stimulation that occur under natural viewing conditions and for understanding the requirements for effective luminance and contrast gain control. Local luminance and contrast were measured in a large set of calibrated 12-bit gray-scale natural images, for a number of analysis patch sizes. For each image and patch size we measured the range of contrast, the range of luminance, the correlation in contrast and luminance as a function of the distance between patches, and the correlation between contrast and luminance within patches. The same analyses were also performed on hand segmented regions containing only “sky”, “ground”, “foliage”, or “backlit foliage”. Within the typical image, the 95% range (2.5–97.5 percentile) for both local luminance and local contrast is somewhat greater than a factor of 10. The correlation in contrast and the correlation in luminance diminish rapidly with distance, and the typical correlation between luminance and contrast within patches is small (e.g., −0.2 compared to −0.8 for 1/ f noise). We show that eye movements are frequently large enough that there will be little correlation in the contrast or luminance on a receptive field from one fixation to the next, and thus rapid contrast and luminance gain control are essential. The low correlation between local luminance and contrast implies that efficient contrast gain control mechanisms can operate largely independently of luminance gain control mechanisms.

Spontaneous bursting and rhythmic activity in the cuneate nucleus of anaesthetized rats

Spontaneous and rhythmic neuronal activity in dorsal column nuclei has long been identified in anesthetized cats. Here, we have studied the spontaneous behavior of cuneate cells in anesthetized rats through extracellular recording, showing that most cuneate neurones recorded (155 of 185) fired spontaneously. Overall, 74% of these spontaneously firing neurones were single-spiking and 26% were bursting. Cells were considered “bursting” when more than 50% of the spontaneous spikes belonged to bursts. Nevertheless, occasional bursts were seen in 33% of spontaneous cuneate cells which were classified as single-spiking. Rhythmic firing was observed in about 14% of both spontaneously bursting and single-spiking cells, and these cells were located close to the obex (±0.5 mm). Although the spike-frequency was mostly in the range 0–15 spikes/s, spontaneous rhythmic activity was circumscribed mainly to the alpha/beta-like range, both in single-spiking (26.1±3.6 Hz, n=16) and bursting cells (19.5±4.1 Hz, n=6). Lemniscal stimulation often activated several antidromic units with the same latency. About 65% of cuneolemniscal cells were spontaneously active and of these, 83% were single-spiking and 11% rhythmic (all single-spiking). In cells that were not antidromically activated from the medial lemniscus, short latency orthodromic responses consistent with excitation by recurrent lemniscal collaterals were often observed following lemniscal activation. Interestingly, only cells completely unresponsive to lemniscal stimulation showed rhythmic bursting. Most spontaneous cells responded with a burst to natural receptive field stimulation, while rhythmic cells became temporally arrhythmic. These results demonstrate, for the first time, that rat cuneate neurones can fire bursts spontaneously. Besides, this bursting activity can be rhythmic. These two properties, and the fact that groups of cuneolemniscal cells share the same conduction velocity, probably imply the reinforcement of temporal and spatial summation at their targets when they are synchronously recruited by the stimulation of overlapping receptive fields.

Effects of systemically administered cocaine on sensory responses to peri‐threshold vibrissae stimulation: individual cells, ensemble activity, and animal behaviour

Previous studies have shown that systemic administration of cocaine transiently alters stimulus-evoked responses of ventral posteromedial (VPM) thalamic neurons. Results from these single-unit electrophysiological studies revealed that cocaine was equally likely to augment or attenuate the magnitude of sensory evoked responses following threshold level stimulation of peripheral receptive fields. In an attempt to clarify the impact of cocaine administration on sensory signal processing, we examined the drug's effects on responses of individual neurons and ensembles of VPM thalamic neurons to sensory stimuli, and performance of subjects in a sensory detection behavioural task. Extracellular responses of single (n = 1 cell/rat) or multiple VPM thalamic neurons (n = 10-40 cells/rat) were monitored before and after cumulative doses of cocaine (0.25-2.0 mg/kg i.v.). Neuronal responses were characterized by assessing the response profile to a range of peri-threshold-level deflections of the optimal whisker on the contralateral face. Drug effects on stimulus-response curves, determined from quantitative analysis of spike train data, indicated that whereas cocaine elicits variable effects at the single cell level, the stimulus-evoked response of the recorded population was likely to increase following lower (0.25-1.0 mg/kg i.v.) doses of cocaine. Furthermore, cocaine preferentially enhanced responses to smaller magnitude deflections of vibrissa, altering the response profile from a mode that accurately conveyed stimulus strength to one that increased detection at the expense of discrimination. Finally, a similar pattern emerged in a behavioural paradigm involving rats trained to detect variable amplitude whisker pad stimulation, suggesting a common action of cocaine that may contribute to the drug's addictive properties.

Oxytocin actions on afferent evoked spinal cord neuronal activities in neuropathic but not in normal rats

A hypothalamic oxytocinergic-descending pathway that reaches the dorsal horn of the spinal cord has been well documented and recently related to states of pain and analgesia. In order to study the action of the neuropeptide oxytocin (OT) on pain-related responses, we compared dorsal horn neuronal responses to electrical and mechanical stimulation of receptive fields in normal and neuropathic rats. Spinal nerve (L5 and L6) ligation (Chung rats) was used to produce experimental neuropathy. Single unit activity was recorded at the L4–L5 level from neurons identified as wide dynamic range presenting latency responses corresponding to A-beta, A-delta, C fibers and also exhibiting post-discharge, and wind-up. We tested intrathecally applied doses of 0.05, 0.1, 1, 2, 5, 10 I.U. of OT. Minor effects on responses to electrical stimulation were present in normal rats. Mechanical responses evoked by von Frey filaments were slightly reduced in normal animals. In neuropathic rats a dose of 1 I.U. produced a significant reduction in C-fibers and post-discharge activities, and doses of 2 I.U. caused a further, pronounced reduction in post-discharge, wind-up, and input values. However, the most marked change was the post-discharge reduction at 10 and 20 min after OT administration. Mechanical responses were significantly reduced in terms of their discharge rate response in neuropathic rats. The contrasting results obtained in normal and neuropathic rats revealed an important distinction between these animals and indicate that plastic changes occur as a consequence of nerve damage. In neuropathic rats, mechanisms involving ascending noxious information to the paraventricular nuclei and descending OT activities could be altered so sensitizing the OT receptors of the spinal dorsal horn cells and could explain our observations. Our results point out an anti-algesic OT effect in neuropathic rats.

Increased responsiveness of rat dorsal horn neurons in vivo following prolonged intrathecal exposure to interferon-γ

Prolonged increases in the level of the pro-inflammatory cytokine interferon-γ occur in the CNS during some disease states associated with persistent pain. Administration of interferon-γ to both humans and rodents has produced pain or pain-related behavior but the underlying mechanisms are unknown. The present study examined the effects of repeated intrathecal administration of interferon-γ on dorsal horn neuronal responses under in vivo conditions. In addition, behavioral effects of interferon-γ treatment were studied. Intrathecal cannulae were implanted into anesthetized rats. Animals then received either 1000 U of recombinant rat interferon-γ in 10μl buffer intrathecally, repeated four times over 8 days, or similarly administered buffer (controls). Interferon-γ-treated animals showed a significant reduction in paw withdrawal threshold to mechanical stimulation of the hind paw. Electrophysiological experiments were performed under halothane anesthesia. Extracellular recordings of spontaneous and evoked responses were obtained from dorsal horn neurons ( n=64) in the lumbar spinal cord. There was a significantly higher proportion of spontaneously active neurons in the interferon-γ-treated animals (50%) when compared with controls (19%). A significantly increased proportion of neurons from interferon-γ-treated animals displayed afterdischarges following both innocuous and noxious mechanical stimulation of the receptive field (brush: 21% in interferon-γ-treated, 3% in controls; pinch: 97% in interferon-γ-treated, 50% in controls). Neurons from interferon-γ-treated animals also showed significantly increased wind-up of action potentials in response to repeated electrical stimulation of the sciatic nerve at C-fiber strength at both 0.5 and 1Hz. Paired-pulse inhibition, evoked through electrical stimulation of the cutaneous receptive field, was significantly decreased in neurons from interferon-γ-treated animals at 50 and 100 ms inter-stimulus intervals. We propose that this demonstrated reduction in inhibition may underlie the enhanced excitatory responses. Such interferon-γ-induced changes in evoked responses may contribute to persistent pain following damage or disease states in the nervous system.

Splanchnic and pelvic mechanosensory afferents signal different qualities of colonic stimuli in mice

Background&Aims: Mechanosensory information from the colon is conducted via lumbar splanchnic nerves (LSN) and sacral pelvic nerves (PN) to the spinal cord. The precise nature of mechanosensory information encoded by each pathway has remained elusive. Here, we characterize and directly compare the properties of mechanosensitive primary afferents from these 2 pathways. Methods: Using a novel in vitro mouse colon preparation, mechanosensitive primary afferents were recorded from the LSN and PN and distinguished based on their response to receptive field stimulation with 3 distinct mechanical stimuli: probing (70 mg–4 g), circular stretch (1–5 g), and mucosal stroking (10–1000 mg). Results: Five different classes of afferent were recorded from the LSN and PN. Three of these classes of afferent (serosal, muscular, and mucosal) were conserved between both pathways; however, their respective proportions, receptive field distributions, and response properties differed greatly. In general, these 3 classes of afferent recorded from the PN responded to lower stimulation intensities, displayed greater response magnitudes, and adapted less completely to mechanical stimulation compared with their LSN counterparts. In addition, the LSN and PN each contain a specialized class of afferent (mesenteric and muscular/mucosal), which is unique to their respective pathway. Conclusions: The splanchnic and pelvic pathways contain distinct populations of mechanosensitive afferents. These afferents are capable of detecting an array of mechanical stimuli and are individually tuned to detect the type, magnitude, and duration of the stimulus. This knowledge contributes to our understanding of the role that these 2 pathways play in conveying mechanical information from the colon.

Naratriptan has a selective inhibitory effect on trigeminovascular neurones at central 5-HT1A and 5-HT(1B/1D) receptors in the cat: implications for migraine therapy.

The triptans are agonists at serotonin (5-HT)1B/1D receptors; however, they are also active at 5-HT1A and 5-HT1F receptors. We conducted this series of experiments to further elucidate the site of action of naratriptan using a well-established animal model of trigeminovascular stimulation. Following electrical stimulation of the superior sagittal sinus of the cat, single cell responses (n=83) were recorded in the trigeminal nucleus caudalis. Most cells (91%) also responded to electrical and mechanical stimulation of cutaneous or mucosal facial receptive fields. The microiontophoretic application of naratriptan resulted in a significant suppression of the response to sagittal sinus stimulation (response suppressed by 47 +/- 4%, P<0.001). The effect of naratriptan was significantly attenuated by application of either the 5-HT(1B/1D) receptor antagonist GR-127935 (P<0.001) or the 5-HT1A antagonist WAY-100635 (P<0.05). The response of single cells to receptive field stimulation was also suppressed by microiontophoretic application of naratriptan, but by only 20 +/- 3%. Intravenous administration of naratriptan resulted in a similar selective suppression of sagittal sinus vs. receptive field responses in trigeminal neurones. These results indicate that naratriptan has a central effect in the trigeminovascular system, selectively inhibiting afferent activity in craniovascular neurones, via both 5-HT(1B/1D) and 5-HT1A receptors.

Neither Spinal γ-Aminobutyric Acid-A nor Strychnine-Sensitive Glycine Receptor Systems Are the Sole Mediators of Halothane Depression of Spinal Dorsal Horn Sensory Neurons

Inhaled anesthetics depress the response of spinal dorsal horn low-threshold (LT) neurons to peripheral receptive field stimulation. Part of that depression may be mediated by anesthetic interactions with gamma-aminobutyric acid type A (GABA(A)) and strychnine-sensitive glycine inhibitory neurotransmitter systems. In this electrophysiological study, we attempted to antagonize halothane depression of LT neurons by administering bicuculline (a competitive GABA(A) antagonist) and/or strychnine (a competitive glycine antagonist) systemically, alone or in combination, to decerebrate, spinal cord-transected rats. We observed that both bicuculline and strychnine, alone or in combination, significantly but only partially reversed halothane depression of LT neuronal responses to receptive field stimulation. The inability of bicuculline and strychnine, alone or in combination, to completely reverse halothane depression suggests that although GABA(A) and glycine systems are involved in the observed halothane depression, additional mechanisms of action are also required for halothane depression of LT spinal sensory neurons. The results of this study support the hypothesis that halothane depression of spinal sensory neurons is mediated, but not completely, by the anesthetic effects on gamma-aminobutyric acid type A and strychnine-sensitive glycine neurotransmitter systems.

Spinal interleukin-6 (IL-6) inhibits nociceptive transmission following neuropathy

Interleukin-6 (IL-6) is a neuropoietic cytokine which is dramatically upregulated following peripheral nerve injury at the site of injury, in the dorsal root ganglion (DRG) and in the spinal cord. The functional effects of IL-6 in nociception in normal conditions and following nerve injury are unclear. Thus the aim of this study was to assess the effect of spinal IL-6 administration on nociceptive transmission in naive, sham-operated and neuropathic (spinal nerve ligation, SNL) rats using in vivo electrophysiology to elucidate the possible role of IL-6 in neuropathic pain. In anaesthetised rats, extracellular recordings were made from individual convergent dorsal horn neurones following electrical and natural (mechanical and thermal) stimulation of peripheral receptive fields. Exogenous spinal IL-6 (100–500 ng) had no significant effect on electrically evoked neuronal responses in naive rats. In contrast, following neuropathy, spinal IL-6 produced a dose-related inhibition of the electrically evoked C-fibre, initial C-fibre and measures of neuronal hyperexcitability (post discharge and wind-up). In addition, spinal IL-6 markedly inhibited mechanical neuronal responses in neuropathic rats. Higher doses of spinal IL-6 also inhibited, to a lesser degree, the initial C-fibre, post discharge and wind-up responses in sham-operated rats. These studies show that following nerve injury the actions of the cytokine alter so that spinal administration of IL-6 elicits anti-nociceptive effects not observed under normal conditions. Moreover, the inhibitory effects of IL-6 on C-fibre activity and neuronal hyperexcitability, suggest IL-6 to be a potential modulator of neuropathic pain.

Nerve injury induces plasticity that results in spinal inhibitory effects of galanin

Galanin is a 29-amino-acid neuropeptide that has been implicated in the processes of nociception. This study examines the effect of exogenous galanin on dorsal horn neurone activity in vivo in the spinal nerve ligation (SNL) model of neuropathic pain. SNL rats but not naive or sham-operated rats exhibited behaviour indicative of allodynia. In anaesthetized rats, extracellular recordings were made from individual convergent dorsal horn neurones following stimulation of peripheral receptive fields electrically or with natural (innocuous mechanical, noxious mechanical and noxious thermal) stimuli. Spinal administration of galanin (0.5–50 μg) caused a slight facilitation of the neuronal responses to natural and electrical stimuli in naive rats and up to a 65% inhibition of neuronal responses in sham-operated rats following 50 μg galanin. In contrast, there was a marked inhibition of up to 80% of responses to both natural and electrical stimuli in SNL rats following spinal galanin administration. These results suggest that following peripheral nerve injury, there is plasticity in the levels of galanin and/or its receptors at spinal cord level so that the effect of exogenous galanin favours inhibitory function.

Response properties of periodontal mechanosensitive neurones in the rat trigeminal sensory complex projecting to the posteromedial ventral nucleus of the thalamus

Unitary discharges from periodontal mechanosensitive (PM) neurones responding to mechanical stimulation of the tooth were recorded from the trigeminal sensory complex in the rat brainstem. Of the PM units recorded, 22% were activated by antidromic stimulation of the contralateral (20%) or ipsilateral (2%) posteromedial ventral nucleus of the thalamus. Although thalamic-projecting neurones were recorded extensively throughout the trigeminal sensory complex, they originated most often in the region from the caudal main sensory nucleus to the rostral subnucleus oralis of the trigeminal spinal tract nucleus. The response latencies of the rostral nucleus units to orthodromic stimulation of peripheral receptive fields and antidromic stimulation of the thalamus were significantly shorter than those of the caudal nucleus units. More than half were single-tooth units originating from incisor teeth. They responded continuously when pressure was applied to the tooth. The magnitude of the response varied with the direction of the stimulus. Maximal responses were obtained when the stimulus was applied labiolingually or vice versa. The threshold for mechanical stimulation of the tooth was less than 0.05 N. The rostrocaudal distribution and response properties of thalamic-projecting PM neurones were very similar to those of non-thalamic-projecting PM units that were not activated by antidromic stimulation of the thalamus.

Local GABA(A) receptor blockade reverses isoflurane's suppressive effects on thalamic neurons in vivo.

Many in vitro effects of volatile anesthetics are known, but the mechanisms of action are still under debate. Because suppression of sensory perception is one of the major goals of general anesthesia, we studied the effects of isoflurane on the processing of somatosensory information in anesthetized rats. Local iontophoretic administration of the gamma-aminobutyric acid-A (GABA(A)) receptor antagonist bicuculline in the thalamic ventral posteromedial nucleus reversed suppressive effects of isoflurane on thalamocortical relay neurons (TCNs). The action potential discharges of TCNs (n = 23) in response to defined mechanical stimulation of receptive fields seen with small concentrations of isoflurane (0.79% +/- 0.01%, mean +/- SEM) were suppressed under large concentrations (1.44% +/- 0.04%). In addition, the tonic response pattern was lost, which initially encoded the information about the stimulus features. In 70% of TCNs, bicuculline administration reestablished the initially present tonic response pattern under large isoflurane concentrations. These results indicate that isoflurane suppresses somatosensory information transfer at the thalamic level in vivo, apparently by enhancing thalamic GABA(A) receptor-mediated inhibition.

Parabrachial Internal Lateral Neurons Convey Nociceptive Messages from the Deep Laminas of the Dorsal Horn to the Intralaminar Thalamus

This study investigates the physiological properties of parabrachial internal lateral (PBil) neurons that project to the paracentral thalamic (PC) nucleus using antidromic activation and single-unit recording techniques in anesthetized rat. We reported here that most of these neurons responded exclusively to the nociceptive stimulation of large receptive fields with a sustained firing that often outlasted the stimulus up to several minutes. These responses were depressed by intravenous morphine. Our results demonstrated a novel spino-PBil-PC pathway, which transmits nociceptive messages to the PC nucleus, which in turn projects to the prefrontal cortex. Recent clinical imaging studies showed the important participation of prefrontal cortex in emotional response to pain. This spino-PBil-PC pathway may explain how nociceptive messages reach the prefrontal cortex and thus trigger unbearable aversive aspects of pain.

Trigeminohypothalamic and reticulohypothalamic tract neurons in the upper cervical spinal cord and caudal medulla of the rat.

Sensory information that arises in orofacial organs facilitates exploratory, ingestive, and defensive behaviors that are essential to overall fitness and survival. Because the hypothalamus plays an important role in the execution of these behaviors, sensory signals conveyed by the trigeminal nerve must be available to this brain structure. Recent anatomical studies have shown that a large number of neurons in the upper cervical spinal cord and caudal medulla project directly to the hypothalamus. The goal of the present study was to identify the types of information that these neurons carry to the hypothalamus and to map the route of their ascending axonal projections. Single-unit recording and antidromic microstimulation techniques were used to identify 81 hypothalamic-projecting neurons in the caudal medulla and upper cervical (C(1)) spinal cord that exhibited trigeminal receptive fields. Of the 72 neurons whose locations were identified, 54 were in laminae I-V of the dorsal horn at the level of C(1) (n = 22) or nucleus caudalis (Vc, n = 32) and were considered trigeminohypothalamic tract (THT) neurons because these regions are within the main projection territory of trigeminal primary afferent fibers. The remaining 18 neurons were in the adjacent lateral reticular formation (LRF) and were considered reticulohypothalamic tract (RHT) neurons. The receptive fields of THT neurons were restricted to the innervation territory of the trigeminal nerve and included the tongue and lips, cornea, intracranial dura, and vibrissae. Based on their responses to mechanical stimulation of cutaneous or intraoral receptive fields, the majority of THT neurons were classified as nociceptive (38% high-threshold, HT, 42% wide-dynamic-range, WDR), but in comparison to the spinohypothalamic tract (SHT), a relatively high percentage of low-threshold (LT) neurons were also found (20%). Responses to thermal stimuli were found more commonly in WDR than in HT neurons: 75% of HT and 93% of WDR neurons responded to heat, while 16% of HT and 54% of WDR neurons responded to cold. These neurons responded primarily to noxious intensities of thermal stimulation. In contrast, all LT neurons responded to innocuous and noxious intensities of both heat and cold stimuli, a phenomenon that has not been described for other populations of mechanoreceptive LT neurons at spinal or trigeminal levels. In contrast to THT neurons, RHT neurons exhibited large and complex receptive fields, which extended over both orofacial ("trigeminal") and extracephalic ("non-trigeminal") skin areas. Their responses to stimulation of trigeminal receptive fields were greater than their responses to stimulation of non-trigeminal receptive fields, and their responses to innocuous stimuli were induced only when applied to trigeminal receptive fields. As described for SHT axons, the axons of THT and RHT neurons ascended through the contralateral brain stem to the supraoptic decussation (SOD) in the lateral hypothalamus; 57% of them then crossed the midline to reach the ipsilateral hypothalamus. Collateral projections were found in the superior colliculus, substantia nigra, red nucleus, anterior pretectal nucleus, and in the lateral, perifornical, dorsomedial, suprachiasmatic, and supraoptic hypothalamic nuclei. Additional projections (which have not been described previously for SHT neurons) were found rostral to the hypothalamus in the caudate-putamen, globus pallidus, and substantia innominata. The findings that nonnociceptive signals reach the hypothalamus primarily through the direct THT route, whereas nociceptive signals reach the hypothalamus through both the direct THT and the indirect RHT routes suggest that highly prioritized painful signals are transferred in parallel channels to ensure that this critical information reaches the hypothalamus, a brain area that regulates homeostasis and other humoral responses required for the survival of the organism.

5-HT 1A and 5-HT 1B/1D receptors are involved in the modulation of the trigeminovascular system of the cat: a microiontophoretic study

Electrical stimulation of the superior sagittal sinus in the cat activated neurones in the trigeminal nucleus caudalis. The mean latency of these responses (10.1 ms) was consistent with activation of Aδ-fibres. Microiontophoretic ejection of either the selective serotonin 1A (5-HT 1A) agonist (+)8-OH-DPAT or the 5-HT 1B/1D agonist alniditan resulted in the reversible suppression of the response to superior sagittal sinus stimulation of 29/46 and 18/20 trigeminal neurones, respectively. The response to sagittal sinus stimulation was suppressed by 39±5% ( n=46) by (+)8-OH-DPAT and 65±5% ( n=20) by alniditan. Microiontophoretic ejection of the selective 5-HT 1A receptor antagonist WAY-100635 significantly antagonised the effect of (+)8-OH-DPAT (effect reduced by 30%, P<0.05). The ejection of GR-127935, a selective 5-HT 1B/1D, antagonist, significantly antagonised the effect of alniditan (effect reduced by 52%, P<0.02). In eight neurones the response to convergent facial receptive field stimulation was also tested in the presence of alniditan. Only 4/8 receptive field responses were suppressed by alniditan (compared to 8/8 sagittal sinus responses) and alniditan had significantly less quantitative effect on the response to receptive field stimulation than on the response to sagittal sinus stimulation in the same neurones (mean reduction 36±14% and 66±8%, respectively, P<0.05). These results suggest that pharmacological modulation of the trigeminovascular system can occur at the first central synapse and that, in addition to 5-HT 1B/1D receptors, 5-HT 1A receptors may be involved in the modulation of sensory neurotransmission in the trigeminovascular system.

Diffuse noxious inhibitory controls in anti-nociception produced by acupuncture and moxibustion on trigeminal caudalis neurons in rats.

Numerous studies have demonstrated that acupuncture and moxibustion induce analgesic effects. This study examined whether diffuse noxious inhibitory controls (DNIC) participated in acupuncture and moxibustion induced-analgesia. Single unit extracellular recordings from neurons in the trigeminal nucleus caudalis of urethane-anesthetized Wistar rats were obtained with a glass micropipette. A total of 52 single units, including 36 wide dynamic range (WDR), 5 nociceptive specific (NS) and 11 low-threshold mechanoreceptive (LTM) units were examined. During noxious test stimulation (cutaneous pinch or electrical stimulation), acupuncture, moxibustion or pinch stimulation was applied as the conditioning stimulus to the remote area of the receptive fields. When the conditioning stimulation induced rapid suppression of noxious receptive field stimulation response, examination revealed that various areas of the entire body were affected and suppression increased in an intensity-dependent manner. These features resemble DNIC phenomena. The suppression was observed on both WDR and NS neurons but not on LTM neurons. Eight of 16 WDR neurons examined were inhibited by acupuncture, five of 14 by moxibustion, and seventeen of 21 by pinching stimulation. Of the NS neurons, one of 2 units examined was suppressed by acupuncture, one of 2 by moxibustion, and two of 3 by pinch stimulation. Pinch stimulation induced the most profound suppression followed by manual acupuncture. Moxibustion induced moderate suppression with a long induction time. These results suggest that DNIC may be involved in the analgesic mechanism of acupuncture and moxibustion.

Functional organization of tactile inputs from the hand in the cuneate nucleus and its relationship to organization in the somatosensory cortex

Central processing of tactile inputs from the hand begins in the main cuneate nucleus and continues in the thalamus and area 3b cortex. Little is known about cuneate functional organization in primates or about how cuneate and area 3b organization are related. In this study, neurophysiologic approaches were used to evaluate how tactile inputs from the hand and adjacent body are organized in the cuneate nucleus of squirrel monkeys. Cuneate data on the organization of hand inputs were then compared with analogous area 3b data from our earlier cortical studies that used the same approaches. Evaluations of several cuneate properties, including (1) responsiveness to tactile stimulation, (2) incidences and sizes of receptive fields, (3) somatotopic progressions, (4) properties of representations, and (5) relationships between functional inputs and cytochrome oxidase staining, suggest that tactile afferents from the hand form consistently organized cuneate representations that, in turn, relate to the parcellated organization of cuneate structural substrates. Comparisons of cuneate and area 3b organization indicate that tactile processing from the brainstem to cortex involves a preservation of tactile responsiveness and somatotopic organization but, in addition, involves transformations that produce receptive field sharpening, suppression of hairy hand inputs, amplification and refinement of glabrous inputs, and relocations of representations. Ascending lemniscal substrates are characterized by cascading excitatory convergence/divergence that increments at successively higher levels between sensory afferents and area 3b. It is suggested that the observed preservations and transformations reflect this organization but, in addition, reflect mechanisms that cause counterbalancing sharpening and suppressions of hand inputs. J. Comp. Neurol. 411:369–389, 1999. © 1999 Wiley-Liss, Inc.