Inhibition of hyperactive trigeminal subnucleus caudalis neurons after experimental trigeminal rhizotomy in response to thalamic sensory relay nucleus stimulation

The effects of thalamic sensory relay nucleus stimulation on the single neuron activity and field potentials within the trigeminal subnucleus caudalis, which is trigeminal equivalent of the dorsal horn were investigated in intact cats as well as in cats subjected to retro-Gasserian rhizotomy 1-6 months before the experiments. Inhibition of nociceptive neural activity and a positive field potential were evoked by thalamic stimulation in the dorsal horn of the intact animals. A positive field potential followed double pulse stimulation with frequencies ranging up to approximately 50 Hz. The inhibitory periods ranged from 60 to 100 ms. Train pulse stimulation with frequencies ranging from 30 to 50 Hz produced long-lasting inhibition of nociceptive neural activity and a positive shift of the field potentials. Essentially identical inhibition of abnormal neural hyperactivity occurring in the rhizotomized dorsal horn was observed. The positive field potential corresponding to this inhibition also displayed characteristics similar to the field potential seen in the intact dorsal horn. These data indicate that the pathways involved in the inhibitory responses induced by thalamic sensory relay nucleus stimulation, unlike some other pain inhibitory systems, can exert their influence even to the dorsal horn which has undergone reorganization of neural circuits after rhizotomy.     

Dorsal raphe stimulation produces inhibitory effect on trigeminal nucleus neurons.

Inhibitory effects of conditioning stimulation of the dorsal raphe nucleus (DR) on the neuron activity in the rostral part of spinal trigeminal nucleus (STN) were studied in cats for the purpose of comparison with the inhibition induced by locus coeruleus (LC) stimulation. DR conditioning stimulation reduced the orthodromic field potential in STN elicited by inferior alveolar nerve stimulation, and enhanced the antidromic field potential in the trigeminal nerve evoked by STN stimulation; but the inhibitory effects of DR stimulation were considerably weaker than those of LC stimulation. In tracking experiments near the raphe nucleus, conditioning stimulation of DR itself produced the most pronounced decrease in the STN field potential. Orthodromic spike number of STN relay neurons was significantly reduced by DR conditioning stimulation; however, the threshold for the conditioning stimulus to the DR was much higher than that to the LC. Antidromic spike generation of the STN neurons was unaltered by conditioning stimulation of both DR and LC. DR stimulation elicited a field potential in STN, which followed high frequency stimuli up to 200 HZ. A single fiber action potential was also obtained in STN by DR stimulation. STN stimulation produced a field potential in DR, which followed high frequency stimuli. It is suggested from these findings that conditioning stimulation of DR produces a direct inhibition of transmission in STN neurons; however, this stimulation has less effect on these neurons than does stimulation of the LC.     

Negative potentials evoked by nucleus reticularis gigantocellularis in the spinal trigeminal tract of the cat

In cats that were precollicularly decerebrated, bilateral elactrical stimulation of the nucleus reticularis gigantocellularis (NRGC) evoked negative potentials in the spinal trigeminal tract at the level of the subnucleus oralis of the spinal trigeminal nuclear complex. These negative potentials exhibited two types of configurations that differed in the slope of the rising and declining phase, duration, and amplitude of the negative wave. They were also found to develop as a function of the reticular stimulus parameters. Thus, they possessed electrophysiologic characteristics similar to the dorsal root potentials induced by comparable reticular activation in the spinal cord. The time course of the NRGC-evoked negative potential paralleled the inhibition of dental pulp-elicited responses in the subnucleus oralis, promoted by the same reticular stimulation. As the dorsal root potential is generally taken to be a manifestation of primary afferent depolarization, it is suggested, by extrapolation, that the NRGC may, at least in part, suppress the transmission of nociceptive signals from the dental pulp by a depolarization of the pulpal afferent fibers.     

Noradrenaline-mediated inhibition by locus coeruleus of spinal trigeminal neurons

Inhibitory effects of conditioning stimulation of the locus coeruleus (LC) on the neuron activity in spinal trigeminal nucleus (STN) were investigated in gallamine-immobilized cats. Field potentials of STN and spike potentials of single relay neurons in STN were orthodromically elicited by ipsilateral alveolar nerve stimulation and antidromically by stimulation of contralateral medial lemniscus. Conditioning stimuli were applied to LC and sensory cortex (SC) at various C-T intervals.

In tracking experiments near the LC region, conditioning stimulation of LC itself produced the most pronounced decrease in amplitude of the STN field potentials. Orthodromic spikes of STN single neurons were significantly reduced by conditioning stimulation of LC as well as SC. In reserpine-treated animals, however, conditioning stimulation of LC failed to produce a decrease in the number of orthodromic spikes, while the inhibitory effect of SC conditioning stimulation remained unaffected. Under these circumstances, intravenous L-dopa and intraventricular noradrenaline reproduced an inhibitory effect of LC conditioning stimulation on orthodromic spike generation, while such an effect was not seen with either dopamine or serotonin. Antidromic spike was unaltered by any of these treatments. Histochemically, catecholamine fluorescence in LC was entirely eliminated after reserpine-treatment, but was restored after L-dopa injection. These results strongly suggest that noradrenaline released from the terminals of neurons originating in LC produces an inhibition of transmission in the STN relay neurons.     

Brain stem terminations of the trigeminal and upper spinal ganglia innervation of the cerebrovascular system: WGA-HRP transganglionic study

The central projections of the nerve fibers innervating the middle cerebral and basilar arteries were investigated by transganglionic tracing of wheat germ agglutinin conjugated with horseradish peroxidase (WGA-HRP) in the rat. WGA-HRP was applied to the exposed basilar and/or middle cerebral arteries. Sections of the brain, trigeminal and upper spinal ganglia were reacted with tetramethylbenzidine for detection of the tracer. The results demonstrate that trigeminal neurons that innervate the middle cerebral artery project to the trigeminal main sensory nucleus, pars oralis, and the dorsocaudal two-fifths of pars interpolaris of the trigeminal brain stem nuclear complex. Terminals were also visible in the ipsilateral nucleus motorius dorsalis nervi vagi (dmnX) and in the lateral nucleus tractus solitarius (nTs) bilaterally at the level of the obex. The ventral periaqueductal gray, including the dorsal raphe and C2 dorsal horn, were also innervated by nerve fibers from the middle cerebral artery. Ipsilateral trigeminal rhizotomy prior to WGA-HRP application over the middle cerebral artery impeded the visualization of nerve terminations throughout the brain stem. Pretreatment with capsaicin reduced the density of labeled neurons and terminals within the trigeminal ganglion and the brain stem, respectively, following WGA-HRP application over the middle cerebral artery. Basilar artery fibers terminate in the C2 dorsal horn, the cuneate nuclei, dmnX, and nTs bilaterally. A few projections were also labeled in the ventral periaqueductal gray. Unilateral upper two spinal dorsal rhizotomy prior to WGA-HRP application over the exposed basilar artery resulted in terminal labeling within the C2 dorsal horn, the cuneate nucleus, dmnX, and nTs contralateral to the rhizotomy, whereas the ipsilateral side was devoid of any labeling. Bilateral superior cervical ganglionectomy prior to WGA-HRP administration to the middle cerebral and basilar arteries did not alter the visualization of nerve terminations throughout the brain stem.     

Postsynaptic inhibition of cat medullary dorsal horn neurons by stimulation of nucleus raphe magnus and other brain stem sites

Sensory responses of neurons in the medullary and spinal cord dorsal horn can be inhibited by stimulation of a number of brain stem regions. These regions include the nucleus raphe magnus (NRM), the nucleus reticularis gigantocellularis (NGC), the nucleus reticularis magnocellularis (NMC), the periaqueductal gray (PAG), and the nucleus cuneiformis (CU). The purpose of this study was to determine whether or not this inhibition is mediated by postsynaptic processes. Experiments were carried out on chloralose-anesthetized cats. The responses of 29 medullary dorsal horn (trigeminal subnucleus caudalis) cells were recorded with carbon-fiber microelectrodes. Included were cells which responded to noxious stimulation (nine cells) as well as cells which responded only to nonnoxious input. The presence of postsynaptic inhibition was tested by two indirect techniques. We studied the effects of conditioning stimulation of the five regions on the latency of antidromically activated cells and also on the firing rate of neurons excited by iontophoretically applied glutamate. Conditioning stimulation was associated with a block or increased latency of antidromic activation in 15 of 18 nociceptive and nonnociceptive neurons. These effects reflect membrane hyperpolarization, presumably resulting from postsynaptic inhibition. Furthermore, conditioning stimulation of these regions inhibited the glutamate-evoked firing of all 11 cells tested, also indicating a postsynaptic type of inhibition of medullary dorsal horn cells. Thus these results indicate that at least part of the inhibition induced by stimulation of the NRM, NGC, NMC, PAG, and the CU probably results from postsynaptic inhibitory mechanisms.     

Neuronal responses to amino acid lontophoresis in the deafferented spinal trigeminal nucleus

Facial paresthesias or anesthesia dolorosa occurring after retrogasserian trigeminal rhizotomy for trigeminal neuralgia have been attributed to neuronal hyperactivity in the deafferented spinal trigeminal complex. To gain insight into the mechanism of the deafferentation hyperactivity, the responses of spinal trigeminal neurons to amino acid iontophoresis via multibarrel micropipets were studied in 20 cats 2 to 4 weeks after unilateral retrogasserian trigeminal rhizotomy. A population of spontaneously hyperactive neurons (type 2) had markedly decreased sensitivity to the exogenous amino acid transmitters. Amino acid hyposensitivity was nonspecific for both excitatory and inhibitory agents, except in a small subgroup (type 2B) which was selectively hyposensitive to γ-aminobutyric acid. Some type 2 neurons were identified as trigeminothalamic projection neurons. Silent (type 1) neurons had normal responses to amino acids compared to those of controls. Endogenous corticofugal inhibition remained intact for all neuronal groups in the deafferented nucleus. The data do not support Cannon's law of denervation hypersensitivity as the mechanism of postrhizotomy hyperactivity, but seem more consistent with transneuronal atrophy in the deafferented spinal trigeminal nucleus.     

Neuronal responses to amino acid iontophoresis in the deafferented spinal trigeminal nucleus.

Facial paresthesias or anesthesia dolorosa occurring after retrogasserian trigeminal rhizotomy for trigeminal neuralgia have been attributed to neuronal hyperactivity in the deafferented spinal trigeminal complex. To gain insight into the mechanism of the deafferentation hyperactivity, the responses of spinal trigeminal neurons to amino acid iontophoresis via multibarrel micropipets were studied in 20 cats 2 to 4 weeks after unilateral retrogasserian trigeminal rhizotomy. A population of spontaneously hyperactive neurons (type 2) had markedly decreased sensitivity to the exogenous amino acid transmitters. Amino acid hyposensitivity was nonspecific for both excitatory and inhibitory agents, except in a small subgroup (type 2B) which was selectively hyposensitive to γ-aminobutyric acid. Some type 2 neurons were identified as trigeminothalamic projection neurons. Silent (type 1) neurons had normal responses to amino acids compared to those of controls. Endogenous corticofugal inhibition remained intact for all neuronal groups in the deafferented nucleus. The data do not support Cannon's law of denervation hypersensitivity as the mechanism of postrhizotomy hyperactivity, but seem more consistent with transneuronal atrophy in the deafferented spinal trigeminal nucleus.     

Evidence for peripheral, but not central modulation of trigeminal cold receptive cells in the rat

The effects of locus coeruleus (LC), periaqueductal grey (PAG) and segmental stimulation (all of which are known to inhibit convergent nociceptive cells), were tested on the activity of cold receptive cells in the trigeminal system of the rat. LC and PAG stimulation from sites which inhibited convergent nociceptive cells had no effect on cells with cold receptive input in the trigeminal nucleus caudalis. Electrical or mechanical segmental stimulation caused suppression of activity in cold receptive trigeminal nucleus neurons. Recording from the trigeminal ganglion showed this suppression to be a property of the primary afferent cold receptors themselves and therefore it is not analogous to the proposed mechanism for the segmental inhibition of convergent nociceptive neurons.     

Tooth pulp-evoked potentials in the trigeminal brainstem nuclear complex

The surface and depth distributions of mandibular canine, tooth pulp-evoked potentials (TPEPs) in the trigeminal brainstem nuclear complex were studied in anesthetized cats. Three pairs of positive-negative waves or components were elicited from each trigeminal brainstem nucleus (main sensory, MSN; oralis, NO; interpolaris, NI; caudalis or medullary dorsal horn, NC). The location and dipole orientation of the current generator source for each pair of components in each nucleus were determined by using the topographic amplitude distribution of TPEPs in both their normal-reference and inverted polarities and the isoelectric contour line. The current sources for all components were the following: MSN--dorsomedial subnucleus; NO--dorsolateral portion; NI--dorsomedial portion; NC--medial part of superficial and intermediate laminae. These loci are consistent with the central terminal zones of mandibular tooth pulp afferents reported in previous neuroanatomical studies. Measurements of mean peak latencies suggest that tooth pulp A beta afferents contribute to the putatively presynaptic (P1-N1) and monosynaptic (P2-N2) components found in all trigeminal brainstem nuclei and that A delta afferents contribute to the later and possibly polysynaptic components (P3-N3) in the same nuclei. The pertinence of these findings to the theory that both non-nociceptive and nociceptive intradental inputs project to rostral and caudal nuclei are discussed.     

Nociceptive spinothalamic tract and postsynaptic dorsal column neurons are modulated by paraventricular hypothalamic activation

Previously, we demonstrated that stimulation of the paraventricular hypothalamic nucleus diminishes the nociceptive dorsal horn neuronal responses, and this decrease was mediated by oxytocin in the rat. In addition, we have proposed that oxytocin indirectly inhibits sensory transmission in dorsal horn neurons by exciting spinal inhibitory GABAergic interneurons. The main purpose of the present study was to identify which of the neurons projecting to supraspinal structures to transmit somatic information are modulated by the hypothalamic-spinal descending activation. In anaesthetized rats, single-unit extracellular and juxtacellular recordings were made from dorsal horn lumbar segments, which receive afferent input from the toe and hind-paw regions. The projecting spinothalamic tract and postsynaptic dorsal column system were identified antidromically. Additionally, in order to label the projecting dorsal horn neurons, we injected fluorescent retrograde neuronal tracers into the ipsilateral gracilis nucleus and contralateral ventroposterolateral thalamic nucleus. Hence, juxtacellular recordings were made to iontophoretically label the recorded neurons with a fluorescent dye and identify the recorded projecting cells. We found that only nociceptive evoked responses in spinothalamic tract and postsynaptic dorsal column neurons were significantly inhibited (48.1 ± 4.6 and 47.7 ± 8.2%, respectively) and non-nociceptive responses were not affected by paraventricular hypothalamic nucleus stimulation. We conclude that the hypothalamic-spinal system selectively affects the transmission of nociceptive information of projecting spinal cord cells.     

Efferent projections from temperature sensitive recording loci within the marginal zone of the nucleus caudalis of the spinal trigeminal complex in the cat

The efferent projections from nucleus caudalis of the spinal trigeminal complex in cats were studied with retrograde and anterograde axonal transport techniques combined with localization of recording sites in the thalamus and marginal zone of nucleus caudalis to innocuous skin cooling. Results showed brainstem projections from nucleus caudalis to rostral levels of the spinal trigeminal complex, to the ventral division of the principal trigeminal nucleus, the parabrachial nucleus, cranial motor nuclei 7 and 12, solitary complex, contralateral dorsal inferior olivary nucleus, portions of the lateral reticular formation, upper cervical spinal dorsal horn and, lateral cervical nucleus. Projections to the thalamus included: a dorsomedial region of VPM (bilaterally) and to the main part of VPM and PO contralaterally. Neuronal activity was recorded in the dorsomedial region of VPM to cooling the ipsilateral tongue. HRP injections in this thalamic region retrogradely labeled marginal neurons in nucleus caudalis. These results show that marginal neurons of nucleus caudalis provide a trigeminal equivalent of spinothalamic projections to the ventroposterior nucleus in cats.     

Mapping of the normal distribution of substance P-like immunoreactivity in the spinal trigeminal nucleus of the cat

Although a recent preliminary report indicated a pattern of substance P-like immunoreactivity within the spinal trigeminal nucleus that is similar to the projection sites for dental afferent fibers, details of this substance P distribution are lacking. Our purpose was to describe in cats the complete normal pattern of this immunoreactivity within each of the spinal trigeminal subnuclei. Special emphasis was given to the distribution of substance P-like immunoreactive axons and terminals located in the rostral subnucleus caudalis and the periobex region of subnucleus interpolaris, as these are regions shown to receive dental afferent fibers. Careful mapping in normal cats showed, within the resolution of the light microscope, a consistent pattern of distribution that included only a portion of the previously identified dental relay sites, but was somewhat broader in certain levels and more restricted in others. The results are compared with those provided by others from regions such as the dorsal horn and subnucleus caudalis of the spinal trigeminal nucleus. The findings also provide an anatomical basis for a recent physiologic report on specific cell types associated with dental nociceptive afferent fibers. This study also provides a baseline control for future investigations of possible changes in substance P-like immunoreactivity that follows various peripheral, including dental and central, lesions.     

Beta-receptor involvement in locus coeruleus-induced inhibition of spinal trigeminal nucleus neurons: Microiontophoretic and HRP studies

Microiontophoretic and HRP studies were performed on cats anesthetized with alpha-chloralose to determine whether or not the locus coeruleus (LC)- and noradrenaline (NA)-induced inhibition of relay neurons in the subnucleus oralis of the spinal trigeminal nucleus (STN) is mediated by beta-adrenergic receptors. The inhibition of orthodromic spike generation upon intracranial trigeminal nerve stimulation by LC conditioning stimulation and microiontophoretically applied NA (100-200 nA) was antagonized during microiontophoretic application of sotalol, a beta-adrenergic antagonist, but not affected by phentolamine, an alpha-adrenergic antagonist. When HRP at doses of 300-500 nA was applied for 5-15 min to the immediate vicinity of the STN relay or interneuron, which was electrophysiologically identified by stimulating the ipsilateral trigeminal nerve and contralateral medial lemniscus, the injection site was localized to an area 0.3 mm in diameter and HRP-reactive cells were found in the ipsilateral LC, dorsal raphe nucleus and periaqueductal gray ventral to the aqueduct. These results strongly suggest that NA released from the nerve terminals of LC cells inhibits transmission in the STN relay neuron via beta-adrenergic receptors.     

Inhibition of nociceptive evoked activity in spinal neurons through a dorsal column-brainstem-spinal loop

In decerebrate-decerebellate cats, dorsal column stimulation (DCst), rostral to bilateral dorsal column cuts, inhibited dorsal horn neurons discharging to various types of nociceptive stimuli. Similar inhibitory effects were observed from conditioning nucleus raphe magnus stimulation. Activation of this dorsal column-brainstem-spinal loop could be part of an important supraspinal "gating' system to account for the alleviation of pain both by DCst and peripheral nerve stimulation in man.     

Systemic morphine reduces the wind-up of trigeminal nociceptive neurons.

We assessed the effects of intravenous morphine on the wind-up of nociceptive neurons of the spinal trigeminal nucleus oralis (Sp5O). Extracellular recordings of Sp5O nociceptive convergent neurons were performed in intact halothane-anesthetized rats. Wind-up of C-fiber-evoked responses was elicited by repetitive electrical stimulation (train of 16 shocks, 0.66 Hz) of their receptive field at C-fiber intensity (3 times the threshold). Wind-up was tested for its sensitivity to morphine (6 mg/kg,i.v.), and the specificity of the effects was verified with naloxone (0.4 mg/kg, i.v.). Nineteen convergent neurons displaying wind-up were recorded. Morphine reduced the wind-up of all but one. In five cases, notwithstanding a reduced wind-up, the neuronal response evoked by the first stimulus in the train (initial input) was unexpectedly increased. Naloxone always antagonized morphine inhibitory effects on the wind-up. When administered systemically, morphine reduced the wind-up of trigeminal nociceptive neurons. This inhibitory effect occurred independently of morphine's ability to affect the initial C-fiber-evoked input. Our findings support the idea that systemic morphine probably blocks wind-up by acting at opioid receptors located postsynaptically to nociceptive primary afferents.     

Diencephalic modulation of activities of raphe-spinal neurons in the cat

The modulatory effects of diencephalic stimulation on the activities of raphe-spinal neurons were studied extracellularly in cats. Among 240 raphe neurons recorded, 57 neurons were activated antidromically by stimulation of the cervical dorsolateral funiculus. These raphe-spinal neurons were found in the caudal raphe nuclei, i.e., the raphe magnus (43 neurons), raphe obscurus (11), raphe pallidus (2), and raphe pontis (1). All of them responded to innocuous and/or noxious peripheral mechanical stimuli with a broad receptive field. The activities of the majority of these neurons were facilitated by trains of pulse stimulation of the rostral periaqueductal gray and the thalamic relay nucleus but not of the thalamic center median nucleus. The facilitation of firing persisted for more than 3 min after the cessation of train pulse stimulation when the stimulation was applied at 20 Hz for 5 to 30 s. This facilitation was not affected by decortication of the sensorimotor area bilaterally. The facilitatory response to periaqueductal gray stimulation was markedly suppressed by systemic administration of naloxone. On the other hand, that of the thalamic relay nucleus stimulation was found to be unaffected. Based on these findings, the mechanisms of pain relief by stimulation of the rostral periaqueductal gray and thalamic relay nucleus reported in human intractable pain appear to relate, at least partly, to the activation of raphe-spinal neurons. However, the paths to raphe-spinal neurons of stimuli from the periaqueductal gray and the thalamic relay nucleus are thought to be independent from each other based on the different effects of naloxone.     

Distribution of gastrin‐releasing peptide in the rat trigeminal and spinal somatosensory systems

Gastrin‐releasing peptide (GRP) has recently been identified as an itch‐specific neuropeptide in the spinal sensory system in mice, but there are no reports of the expression and distribution of GRP in the trigeminal sensory system in mammals. We characterized and compared GRP‐immunoreactive (ir) neurons in the trigeminal ganglion (TG) with those in the rat spinal dorsal root ganglion (DRG). GRP immunoreactivity was expressed in 12% of TG and 6% of DRG neurons and was restricted to the small‐ and medium‐sized type cells. In both the TG and DRG, many GRP‐ir neurons also expressed substance P and calcitonin gene‐related peptide, but not isolectin B₄. The different proportions of GRP and transient receptor potential vanilloid 1 double‐positive neurons in the TG and DRG imply that itch sensations via the TG and DRG pathways are transmitted through distinct mechanisms. The distribution of the axon terminals of GRP‐ir primary afferents and their synaptic connectivity with the rat trigeminal sensory nuclei and spinal dorsal horn were investigated by using light and electron microscopic histochemistry. Although GRP‐ir fibers were rarely observed in the trigeminal sensory nucleus principalis, oralis, and interpolaris, they were predominant in the superficial layers of the trigeminal sensory nucleus caudalis (Vc), similar to the spinal dorsal horn. Ultrastructural analysis revealed that GRP‐ir terminals contained clear microvesicles and large dense‐cored vesicles, and formed asymmetric synaptic contacts with a few dendrites in the Vc and spinal dorsal horn. These results suggest that GRP‐dependent orofacial and spinal pruriceptive inputs are processed mainly in the superficial laminae of the Vc and spinal dorsal horn. J. Comp. Neurol. 522:1858–1873, 2014. © 2013 Wiley Periodicals, Inc.     

Effects of L-threo-DOPS, an L-noradrenaline precursor, on locus coeruleus-originating neurons in spinal trigeminal nucleus

Electrophysiological studies using reserpinized cats were performed to examine the effects of L-threo-3,4-dihydroxyphenylserine (L-threo-DOPS) on the noradrenergic pathway from the locus coeruleus (LC) to the spinal trigeminal nucleus (STN). The spike generation of STN relay neurons induced by trigeminal nerve stimulation was not affected by LC conditioning stimulation nor iontophoretic application of L-threo-DOPS. After intraventricular administration of L-threo-DOPS, the inhibition of the spike generation was seen with LC conditioning stimulation and blocked by iontophoretically applied sotalol, suggesting that L-noradrenaline converted from L-threo-DOPS inhibits transmission of STN relay neurons.     

Altered local cerebral glucose utilization induced by electrical stimulations of the thalamic sensory and parafascicular nuclei in rats

Alterations in local cerebral glucose utilization (LCGU) induced by electrical stimulation of the sensory relay nucleus (VPL) or parafascicular nucleus (Pf) of the thalamus in conscious rats were measured by the [14C]2-deoxyglucose method, the objective being to assess the mechanism of analgesia induced by electrical stimulations of these structures. Stimulation of the VPL induced an ipsilateral increase in LCGU in the sensory thalamic nucleus itself, the sensory cortex and substantia nigra. Stimulation of the Pf induced bilateral increases in LCGU in the Pf and central medial nucleus of the thalamus, sensory cortex, ventral areas of the striatum and substantia nigra, and ipsilateral increase in LCGU in the periaqueductal gray, parabrachial pontine nucleus and deep layers of the superior colliculus. No significant change in LCGU was detected in the raphe dorsalis, raphe magnus and spinal dorsal horn, in both groups. Our observations coincide with clinical findings that unilateral electrical stimulation of the Pf leads to amelioration of intractable pain bilaterally, while that of the VPL induces an analgesia restricted to the contralateral side.