Central mechanism of an extensive analgesic effect due to strong electroacupuncture of acupoint on spinal dorsal horn neurons]

Experiments were performed on male rats. The responses of dorsal horn convergent neurons in spinal cord (T12-L1) to noxious stimulation of hind paw were recorded extracellularly with glass microelectrode. When low intensity (2 V) electroacupuncture (EA) was used, the nociceptive responses of convergent neurons were inhibited by EA at "Zusanli" near noxious stimulation area, but not at "Xiaguan" far from the area. When intensity (18 V) high than the threshold of C fibers EA was applied at the far acupoint "Xiaguan", obvious analgesic effects on convergent neurons were also produced, showing an extensive analgesic effect of strong EA at acupoint. This extensive analgesic effect was abdicated by lesion of nucleus raphe magnus (NRM), but still persisted to some extent by EA at the same segment acupoint "Zusanli" with 18 V or 2 V intensity. The results suggest that, the extensive analgesia of strong EA at far segment acupoint may be mainly mediated by noxious stimulation through NRM, a negative feedback mechanism modulating pain of supraspinal cord. The analgesia due to 2 V EA at the same segment acupoint may be mainly produced by gate control in spinal cord, but also to some extend by supraspinal cord mechanism.     

Effect of local standards on the implementation of national guidelines for asthma: primary care agreement with national asthma guidelines

In vivo electrophysiological assays in anesthetized rats have been used to compare the effects of the 5HT1B/1D receptor agonist, naratriptan, on central trigeminal nociceptive processing from dural and cutaneous inputs with its effects on nociceptive processing in the spinal cord. Naratriptan inhibited responses of single trigeminal neurons, to noxious electrical and mechanical stimulation of the dura and face, dose dependently by a maximum of 67+/-3% and 70+/-18%, respectively, at 3 mg kg(-1) i.v. In contrast, naratriptan did not affect spinal dorsal horn neuronal responses to noxious mechanical stimulation of the hind-paw. These findings suggest that 5HT1B/1D receptors have differential effects on nociceptive processing in the trigeminal versus spinal dorsal horns and provide a potential explanation for the lack of general analgesic effects of brain penetrant 5HT(1B/1D) agonist antimigraine drugs.     

Considerations in the determination by microdialysis of resting extracellular amino acid concentrations and release upon spinal cord injury

The following issues are further addressed: (1) Is there considerable leakage of amino acids from the circulation into the space around microdialysis probes, or are amino acid concentrations naturally much higher in the interstitial space than is generally thought? (2) Do observed high interstitial concentrations or depletion of substances in the intracellular space by microdialysis affect release measurements upon spinal cord injury? Amino acid concentrations around microdialysis fibres in the spinal cord of rats were found to approach those in the circulation and to be much higher than interstitial concentrations previously estimated in the CNS. However, much lower concentrations of amino acids were derived in the hippocampus by analogous experiments. Considerable Evans Blue/albumin leaked from the circulation into the interstitial space in the spinal cord immediately after fibre insertion. However, this movement diminished considerably by 4 h later, demonstrating substantial resealing of the blood-brain barrier, at least to large molecules. There is either substantial damage-induced movement of amino acids from the circulation into the dialysis zone after insertion of a microdialysis probe, or there is much less impediment to movement of amino acids across the blood-brain barrier in the spinal cord than in the brain. At low flow rates through the fibre, adding concentrations of amino acids to the inside of the fibre equal to the concentrations around the fibre to prevent their depletion by removal through the microdialysis fibre did not affect increases in concentrations of amino acids in microdialysates following injury. Thus the high concentrations of amino acids present around microdialysis fibres following their insertion do not seem to disturb measurements of amino acid release upon spinal cord injury.     

Interactions between excitatory amino acids and tachykinins in the rat spinal dorsal horn

Whole-cell patch-clamp technique of freshly isolated rat spinal dorsal horn (DH) neurons, intracellular recording from DH neurons in a slice preparation, and high performance liquid chromatography with fluorimetric detection of release of endogenous glutamate and aspartate from spinal cord slice following activation of primary afferent fibers were employed to investigate interactions between excitatory amino acids (EAA) and tachykinins [substance P (SP) and neurokinin A (NKA)]. Potentiation of N-methyl-D-aspartate (NMDA)-, quisqualate (QA)- and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-, but not kainate-induced currents by SP and NKA was found. Spantide II, a claimed novel nonselective tachykinin antagonist, effectively blocked the SP (2 nM)-induced potentiation of the responses of DH neurons to NMDA. In the presence of glycine (0.1 microM), the SP-evoked increase of the NMDA-induced current was prevented. However, 7-chlorokynurenic acid (2 microM), a competitive antagonist at the glycine allosteric site of the NMDA receptor, led to the reestablishment of the SP effect. Brief high frequency electrical stimulation of primary afferent fibers produced a long-lasting potentiation of presumed monosynaptic and polysynaptic excitatory postsynaptic potentials and sustained enhanced release of endogenous glutamate (218.3 +/- 66.1%) and aspartate (286.3 +/- 58.0%). Possible functional implications of the observed phenomena are discussed in relation to transmission and integration of sensory information, including pain.     

Physiology of nociception

Nociception is related to the mechanisms elicited by stimuli threatening the integrity of the organism. At the peripheral level, unmyelinated C fibres (C polymodal nociceptores) or fine myelinated A delta fibres are excited by noxious stimulation, directly or indirectly by inflammatory processes. Nociceptive afferent fibres terminate in the superficial laminae of the dorsal horn of the spinal cord where informations are integrated and controlled. These first synapses are modulated by excitatory amino acids (glutamate and aspartate) and many peptides (substance P, CGRP, CCK, endogenous opiods). The majority of ascending pathways involved in nociception are located in the ventrolateral controlateral quadrant of the cord (spinorelicular and spinothalamic tracts). Many supraspinal sites are activated following nociceptive stimuli, with relays in the reticular formation of the brain stem (including the subnucleus reticularis dorsalis), the ponto-mesencephalic regions (periaqueducal gray matter and parabrachial area) and thalamic sites. Amygdala and hypothamic targets could be involved in motivational reactions and neuroendocrine adaptations to a noxious event. The cingular, insular and somatosensory cortices also receive nociceptive informations. Nociceptive signals are modulated at all levels of their transmission; the more extensively studied controls are located at the spinal level. Segmental controls are inhibitory effects produced by non-noxious mechanical stimuli. Spinal signals can also be inhibited following activation of bulbopinal descending inhibitor pathways and release of serotonin, norepinephrine and, indirectly, endogenous opiods. Inhibitory controls triggered by noxious stimuli could facilitate the extraction of the nociceptive tone of informations having priority over other stimuli.     

Neonatal capsaicin treatment abolishes formalin-induced spinal PGE2 release

We investigated the effect of neonatal capsaicin treatment on formalin-evoked pain behavior and spinal levels of nociceptive neuromodulators using in vivo intrathecal microdialysis in conscious adult rats and age-matched controls. Capsaicin-treated rats displayed thermal hypoalgesia and a significant decrease in tissue content of calcitonin gene-related peptide. Paw swelling, flinching and release of spinal prostaglandin E2 induced by injection of formalin into the hindpaw were also reduced in capsaicin-treated rats compared with controls, whereas glutamate, aspartate and taurine release was unaffected. These data suggest that formalin-induced inflammation, pain behavior and spinal prostaglandin E2 release are mediated by mechanisms sensitive to neonatal capsaicin while the formalin-evoked release of amino acids in the spinal cord is not.     

Spinal amino acid release and precipitated withdrawal in rats chronically infused with spinal morphine

Glutamate receptors are implicated in the genesis of opioid tolerance and dependence. Factors governing release of amino acids in systems chronically exposed to opiates, however, remain undefined. Using rats, each prepared with a spinal loop dialysis catheter and with a chronic lumbar intrathecal infusion catheter connected to a subcutaneous minipump, the release of amino acids before and during antagonist-precipitated withdrawal in unanesthetized rats was examined. Spinal infusion of morphine (20 nmol/micro l/hr) for 4 d had little effect on resting release of amino acids. In morphine-infused, but not saline-infused, rats naloxone (2 mg/kg, i.p.) evoked an immediate increase in the release of L-glutamate (299 +/- 143%) and taurine (306 +/- 113%) but not other amino acids. The magnitude and time course of the release of these amino acids significantly correlated with behavioral indices of withdrawal intensity. Acute intrathecal pretreatment immediately before naloxone with clonidine (20 microg; alpha2 agonist), MK-801 (3 microg; noncompetitive NMDA antagonist), or aminophosphonopentanoic acid (AP-5; 3 microg; competitive NMDA antagonist) suppressed naloxone-induced increases in spinal L-glutamate and taurine release and behavioral signs of withdrawal in spinal morphine-infused rats. Results point to a correlated increase in spinal L-glutamate release, which contributes to genesis of the opioid withdrawal syndrome. Agents such as clonidine that suppress opioid withdrawal may owe their action to an inhibition of excitatory amino acid release. The effects of MK-801 and AP-5 suggest a glutamate-evoked glutamate release.     

Construction of a DNA library from chromosome 4 of rice (Oryza sativa) by microdissection

To evaluate the role of excitatory amino acids in secondary injury occurring after spinal cord trauma, several experimental studies focusing on the the changes of amino acid levels in the spinal cord have been performed to date. However, because of technical limitations, it has not been possible to correlate the local changes of excitatory amino acids with the total tissue levels of excitatory amino acids. To investigate the connection between the spread of injury and the excitatory amino acids, we assessed, the local changes of aspartate through novel experimental approaches like immunoreactivity via fluorescence microphotometry and histopathology while also analyzing the total tissue levels of amino acids via HPLC. These studies were performed using a model of incomplete cervical spinal cord injury in rats. Through this approach, we found that the levels of excitatory amino acids, such as glutamate and aspartate, began to decrease immediately after injury. No significant decrease was observed in the other amino acids. Similarly, local changes in aspartate in the spinal cord were observed using fluorescence microphotometry. The decrease in the anterior and posterior horns was rapid up to 15 min after injury, but, slowed thereafter, suggesting that a release of excitatory amino acids occurred at the site of primary injury almost immediately following injury. At 15-min post-injury large neurons within the injured cord appeared intact on histopathological analysis demonstrating that the alteration of excitatory amino acids occurs prior to histopathological change. Histopathological change in the white matter occurred more slowly than in the anterior and posterior horns, suggesting the spread of the lesion by secondary damage due to an autoclastic mechanism.     

Primary afferent-evoked release of immunoreactive galanin in the spinal cord of the neuropathic rat

We have determined if peripheral nerve stimulation altered the increased spontaneous release of immunoreactive (ir)-galanin that is found in the superficial dorsal horn of the spinal cord of neuropathic rats. Using the antibody microprobe technique to study the localized sites of ir-galanin release in vivo, we found that high intensity electrical stimulation of the injured nerve resulted in a further increase in ir-galanin release in the superficial dorsal horn, with no significant persistence of ir-galanin after release. Release of ir-galanin at stimulus strengths sufficient to activate C fibres, in an area of the spinal cord thought to be concerned with nociceptive transmission, indicates a possible role for this peptide in the spinal modulation of pain after peripheral nerve injury.     

The vesicular GABA transporter, VGAT, localizes to synaptic vesicles in sets of glycinergic as well as GABAergic neurons

A transporter thought to mediate accumulation of GABA into synaptic vesicles has recently been cloned (McIntire et al., 1997). This vesicular GABA transporter (VGAT), the first vesicular amino acid transporter to be molecularly identified, differs in structure from previously cloned vesicular neurotransmitter transporters and defines a novel gene family. Here we use antibodies specific for N- and C-terminal epitopes of VGAT to localize the protein in the rat CNS. VGAT is highly concentrated in the nerve endings of GABAergic neurons in the brain and spinal cord but also in glycinergic nerve endings. In contrast, hippocampal mossy fiber boutons, which although glutamatergic are known to contain GABA, lack VGAT immunoreactivity. Post-embedding immunogold quantification shows that the protein specifically associates with synaptic vesicles. Triple labeling for VGAT, GABA, and glycine in the lateral oliva superior revealed a higher expression of VGAT in nerve endings rich in GABA, with or without glycine, than in others rich in glycine only. Although the great majority of nerve terminals containing GABA or glycine are immunopositive for VGAT, subpopulations of nerve endings rich in GABA or glycine appear to lack the protein. Additional vesicular transporters or alternative modes of release may therefore contribute to the inhibitory neurotransmission mediated by these two amino acids.     

ATP P2x receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats

ATP P2x receptors and sensory synaptic transmission between primary afferent fibers and spinal dorsal horn neurons in rats. J. Neurophysiol. 80: 3356-3360, 1998. Glutamate is a major fast transmitter between primary afferent fibers and dorsal horn neurons in the spinal cord. Recent evidence indicates that ATP acts as another fast transmitter at the rat cervical spinal cord and is proposed to serve as a transmitter for nociception and pain. Sensory synaptic transmission between dorsal root afferent fibers and neurons in the superficial dorsal horn of the lumbar spinal cord were examined by whole cell patch-clamp recording techniques. Experiments were designed to test if ATP could serve as a transmitter at the lumbar spinal cord. Monosynaptic excitatory postsynaptic currents (EPSCs) were completely abolished after the blockade of both glutamatergic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate and N-methyl--aspartate receptors. No residual current was detected, indicating that glutamate but not ATP is a fast transmitter at the dorsal horn of the lumbar spinal cord. Pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS), a selective P2x receptor antagonist, produced an inhibitory modulatory effect on fast EPSCs and altered responses to paired-pulse stimulation, suggesting the involvement of a presynaptic mechanism. Intrathecal administration of PPADS did not produce any antinociceptive effect in two different types of behavioral nociceptive tests. The present results suggest that ATP P2x2 receptors modulate excitatory synaptic transmission in the superficial dorsal horn of the lumbar spinal cord by a presynaptic mechanism, and such a mechanism does not play an important role in behavioral responses to noxious heating. The involvement of other P2x subtype receptors, which is are less sensitive to PPADS, in acute nociceptive modulation and persistent pain remains to be investigated.     

The organization and function of endogenous antinociceptive systems

Much progress has been made the understanding of endogenous pain-controlling systems. Recently, new concepts and ideas which are derived from neurobiology, chaos research and from research on learning and memory have been introduced into pain research and shed further light on the organization and function of endogenous antinociception. These most recent developments will be reviewed here. Three principles of endogenous antinociception have been identified, as follows. (1) Supraspinal descending inhibition: the patterns of neuronal activity in diencephalon, brainstem and spinal cord during antinociceptive stimulation in midbrain periaqueductal gray (PAG) or medullary nucleus raphe magnus have now been mapped on the cellular level, using the c-Fos technique. Results demonstrate that characteristic activity patterns result within and outside the PAG when stimulating at its various subdivisions. The descending systems may not only depress mean discharge rates of nociceptive spinal dorsal horn neurons, but also may modify harmonic oscillations and nonlinear dynamics (dimensionality) of discharges. (2) Propriospinal, heterosegmental inhibition: antinociceptive, heterosegmental interneurons exist which may be activated by noxious stimulation or by supraspinal descending pathways. (3) Segmental spinal inhibition: a robust long-term depression of primary afferent neurotransmission in A delta fibers has been identified in superficial spinal dorsal horn which may underlie long-lasting antinociception by afferent stimulation, e.g. by physical therapy or acupuncture.     

Effect of spinal kainic acid receptor activation on spinal amino acid and prostaglandin E2 release in rat

Current work has shown that spinal excitatory amino acid receptor activation can evoke physiological phenomena that may be mediated by the subsequent depolarization of glutamate-containing neurons and the activation of cyclo-oxygenase systems. To investigate this phenomenon, rats were implanted with lumbar intrathecal loop dialysis catheters for perfusion and an additional lumbar intrathecal PE-10 catheter for drug delivery. Two days after implantation, kainic acid (1 microgram) was injected intrathecally under light (0.5%) halothane anaesthesia and the spinal release of several amino acids and prostaglandin E2 was examined. Resting concentrations (mean expressed as pmol/25 microliters) of glutamate (89), aspartate (9), serine (387), glycine (597), taurine (185), asparagine (113) and prostaglandin E2 (0.43) were observed. Intrathecal kainic acid produced significant signs of arousal in the rat and evoked a significant increase (mean +/- S.E.M. of % baseline concentration) in aspartate (445 +/- 127%) and glutamate (221 +/- 35%). Prostaglandin E2 concentration was increased in the second post-injection sample (180 +/- 36%). Intrathecal pretreatment with 6-cyano-7-nitroquinoxaline-2, 3-dione (3 micrograms or 10 micrograms), a non-N-methyl-D-aspartate receptor antagonist, blocked amino acid but not prostaglandin E2 release after kainic acid injection. Pretreatment with MK-801 (10 micrograms; non-competitive NMDA receptor antagonist) had no significant effect on evoked release of amino acids or prostaglandin E2. Indomethacin (10 micrograms, a cyclo-oxygenase inhibitor) pretreatment significantly decreased baseline prostaglandin E2 release in control animals (61 +/- 6%) and suppressed kainic acid-evoked aspartate, taurine and prostaglandin E2 release, but had no effect on the concentration of glutamate after kainic acid injection. These data suggest that activation of spinal kainic acid receptors provides a powerful stimulus for secondary excitatory amino acid release and, consistent with the concurrent appearance of prostaglandin E2, that this release is potentiated by the release of a cyclo-oxygenase product.     

Pain in a Balance: Noxious Events Engage Opposing Processes That Concurrently Modulate Nociceptive Reactivity.

Studies have shown that noxious cutaneous stimulation engages physiologically different antinociceptive systems to inhibit a spinal reflex, tail withdrawal from radiant heat. Two experiments are reported that examine the relationship between the inhibition of the tail-flick response and brain-mediated responses to nociception. The induction of a spinally mediated antinociception was accompanied by an increase in latency to vocalize to a noxious thermal stimulus, suggesting pain inhibition. Physiological manipulations that eliminated the inhibition of the tail-flick reflex restored vocalization to thermal stimulation and revealed a concurrent sensitization that generally heightened behavioral reactivity. The results suggest that net pain is regulated by 2 opposing processes, a selective inhibition of nociceptive signals within the spinal cord and a general sensitization that heightens stimulus processing. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Spinal serotonergic receptors mediate facilitation of a nociceptive reflex by subcutaneous formalin injection into the hindpaw in rats

It is documented that spinal nociceptive transmission receives descending facilitatory and inhibitory modulation from supraspinal structures. The rostral ventral medulla (RVM), including the nucleus raphe magnus (NRM), nuclei reticularis gigantocellularis (NGC) and gigantocellularis pars alpha (NGCalpha), is the major bulbar relay of descending modulatory influences. Pharmacological studies show that facilitation of a spinal nociceptive tail-flick (TF) reflex induced by stimulation in the NGC and NGCalpha is mediated by spinal serotonergic receptors. The present series of experiments provide evidence that activation of spinal serotonergic systems are critical for both induction and maintenance of secondary hyperalgesia induced by subcutaneous injection of formalin into one hindpaw. Subcutaneous injection of formalin produced facilitation of tail withdrawal (mechanical) and the TF reflex (thermal). Facilitatory effects persisted for at least 30 min. Peripheral blockade of the activity by local injection of a hydrophilic lidocaine derivative (QX-314, 5%) into the injected hindpaw abolished both mechanical and thermal facilitation, indicating that peripheral input is important to maintain long-lasting facilitation. Intrathecal application of a serotonergic receptor antagonist methysergide at a dose (64 nmol) which completely blocked descending facilitation produced by electrical- or chemical-stimulation in the NGC and NGCalpha also significantly attenuated or completely abolished facilitation of tail withdrawal and the TF reflex induced by formalin. Methysergide was effective whether the injection was performed before or after the formalin injection. These results suggest that activation of descending facilitatory serotonergic influences by a prolonged noxious stimulation could contribute to secondary hyperalgesia observed at the tail.     

Qualitative and quantitative analysis of glycine- and GABA-immunoreactive nerve terminals on motoneuron cell bodies in the cat spinal cord: a postembedding electron microscopic study

The distribution of glycine- and gamma-aminobutyric acid (GABA)-like immunoreactivity (LI) in nerve terminals on the cell soma of motoneurons in the aldehyde-fixed cat L7 spinal cord was examined using postembedding immunogold histochemistry in serial ultrathin sections. Quantitative examination of 405 terminals on eight neurons of alpha-motoneuron size in the L7 motor nuclei from one animal was performed. A majority of the terminals (69%) were immunoreactive to glycine and/or GABA. These terminals contained flat or oval synaptic vesicles, thus classifying them as F type or as C type in one case. In no case was a type-F terminal unlabeled for both glycine and GABA. Most of the immunolabeled terminals were immunoreactive to glycine only (62.5%), whereas 35.4% contained both glycine- and GABA-LI. A very small number of immunolabeled terminals (2%) were immunoreactive to GABA only. In those terminals, where glycine- and GABA-LI coexisted, the gold particle density for each amino acid was only half of that seen in boutons containing only one of the two amino acids. The involvement of glycine and GABA in postsynaptic inhibition of spinal alpha-motoneurons is discussed, with particular reference to the possibility that these two inhibitory amino acids may be coreleased from a significant proportion of the nerve terminals impinging on the cell bodies.     

Brain-derived neurotrophic factor stimulates hindlimb stepping and sprouting of cholinergic fibers after spinal cord injury

Neurotrophic factors have been proposed as a therapeutic treatment for traumatic brain and spinal cord injury. The present study determined whether exogenous administration of one such factor, brain-derived neurotrophic factor (BDNF), could effect behavioral recovery and/or histopathological changes after spinal cord injury. Adult rats received a mild or moderate contusion injury or complete transection of the mid-thoracic spinal cord. Immediately thereafter, they were infused intrathecally with vehicle or BDNF for 28 days. Behavioral recovery was evaluated for 6 weeks after injury, at which time the rats were sacrificed and the spinal cord tissue was examined histologically. The infusion of BDNF resulted in acute stimulation of hindlimb activity. These effects included activation of alternating airstepping in injured rats when the hindlimbs were unloaded as well as slight improvements in the rate of recovery in open field locomotion score. BDNF infusion was also associated with enhanced growth of cholinergic fibers at the injury epicenter, but did not affect white matter sparing or density of serotonergic axons at or below the injury site. Based on immunohistochemical detection of BDNF protein distribution, these described effects are likely to be mediated by the activation of cells and axons within the central injury region and the along the peripheral rim of the spinal cord. Together, these findings demonstrate that the exogenous infusion of BDNF after spinal trauma can influence postinjury outcome through mechanisms that include acute stimulation of hindlimb activity and neuritogenesis at the injury site.     

Release of exqenous glycine in the pigeon optic tectum during stimulation of a midbrain nucleus

A pathway having an affinity for glycine has been investigated in the pigeon optic lobe; it originates in the nucleus isthmi pars parvocellularis (Ipc) and terminates in the tectum, In an attempt to obtain evidence that glycine plays a role as a transmitter in this system, the effect of electrical stimulation on release of labeled substances previously injected in the tectum was tested. By perfusing the upper strata of the optic tectum with a push-pull cannula the release of radioactive glycine was shown to be markedly increased by electrical stimulation of Ipc, but not by stimulation of other sites. Ipc stimulation did not affect the efflux of exogenous leucine or urea, whereas a GABA release was observed. With K+ (40 mM) stimulation all amino acids tested were released. It is suggested that the Ipc neuron terminals in the tectum take up glycine and release it upon stimulation of the Ipc nucleus.     

Nociceptive c-fos expression in supraspinal areas in avoidance of descending suppression at the spinal relay station

The number and distribution of Fos-like-immunoreactive neurons in different supraspinal brain areas induced by formalin injection into one hindpaw was estimated in rats with transected dorsal half of the spinal cord at the thoracic level in an attempt to avoid most of the descending modulatory actions. The results showed that: (i) after spinal lesion, the peripheral noxious inputs, going up mainly through the ventral spinal cord, elicited a more widespread and densely located Fos-like-immunoreactive neurons in subcortical areas, many of them showed no Fos expression when noxious stimulation was given in rats with intact spinal cord; (ii) at the same time, a small number of subcortical areas, such as the lateral ventroposterior thalamic nucleus and dorsal raphe nucleus, exhibited no significant increase of nociceptive Fos-like immunoreactive neurons after spinal lesion as compared to that with intact spinal cord; and (iii) there appeared a prominent expansion of cortical areas with densely located Fos-like-immunoreactive neurons in spinal-lesioned rats as compared with the limited labelled areas in the control group with intact spinal cord. These results indicate that: (i) in avoiding the spinally descending modulatory mechanisms, more widespread supraspinal and cortical neurons will be recruited and activated in response to the noxious stimulation; and (ii) the descending systems exert differential actions on the spinal targets which project nociceptive signals to different supraspinal regions. The implication of these facts is discussed.