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

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Parabrachial Internal Lateral Neurons Convey Nociceptive Messages from the Deep Laminas of the Dorsal Horn to the Intralaminar Thalamus The Journal of Neuroscience, March 15, 2001, 21(6):2159–2165 Parabrachial Internal Lateral Neurons Convey Nociceptive Messages from the Deep Laminas of the Dorsal Horn to the Intralaminar Thalamus Laurence Bourgeais, Le´ naı¨c Monconduit, Luis Villanueva, and Jean-Franc¸ ois Bernard Institut National de la Sante´ et de la Recherche Me´ dicale U-161, F-75014 Paris, France This study investigates the physiological properties of parabra- which in turn projects to the prefrontal cortex. Recent clinical chial internal lateral (PBil) neurons that project to the paracen- imaging studies showed the important participation of prefron- tral thalamic (PC) nucleus using antidromic activation and tal cortex in emotional response to pain. This spino–PBil–PC single-unit recording techniques in anesthetized rat. We re- pathway may explain how nociceptive messages reach the ported here that most of these neurons responded exclusively prefrontal cortex and thus trigger unbearable aversive aspects to the nociceptive stimulation of large receptive fields with a of pain. sustained firing that often outlasted the stimulus up to several minutes. These responses were depressed by intravenous Key words: parabrachial area; thalamus; intralaminar nuclei; morphine. paracentral nucleus; dorsal horn; nociception Our results demonstrated a novel spino–PBil–PC pathway, which transmits nociceptive messages to the PC nucleus, Old clinical reports (Freeman and Watts, 1948), as well as more V/VI of the spinal cord (Kitamura et al., 1993; Bernard et al., recent brain imaging studies (Rainville et al., 1997), demon- 1995; Feil and Herbert, 1995); it projects to the PC and to a lesser strated that the prefrontal cortex plays an important role in the extent in other intralaminar thalamic nuclei (see also Fulwiler processing of aversive component of pain. However, the pathways and Saper, 1984; Hermanson and Blomqvist, 1997b; Bester et al., that carry the nociceptive information to this brain region remain 1999), and noxious stimulation evoked a marked expression of poorly understood. The spinothalamic tract projects primarily to phospho-cAMP response element-binding protein in and around the sensory relay nuclei in the “lateral” thalamus and only mod- the PBil (Hermanson and Blomqvist, 1997a). In this study, we erately to the “medial” thalamic nuclei, which in turn project to investigated the physiological properties of PBil neurons that the prefrontal regions (Willis et al., 1995). It is generally believed project to the PC nucleus using antidromic stimulation and single- that laminas V/VI of the dorsal horn (a major link of the noci- unit recording techniques. ceptive system; Besson and Chaouch, 1987) reach the medial thalamus rather indirectly via spino–reticulo–thalamic pathways. MATERIALS AND METHODS The two main candidates to convey nociceptive messages from Animal preparation. Experiments were performed on 59 Sprague Dawley the deep spinal laminas to the medial thalamus are the giganto- male rats weighing 250–300 gm. The animals were deeply anesthetized with 2% halothane in a nitrous oxide/oxygen mixture (2:3–1:3), para- cellular reticular (Gi) nucleus (Casey, 1971; Bowsher, 1976) and lyzed by an intravenous injection of gallamine triethiodide (Flaxedil), the subnucleus reticularis dorsalis (SRD), in the medulla (Villa- and artificially ventilated using a Palmer pump. The expiratory end tidal ϳ Ϯ nueva et al., 1996, 1998). Nonetheless, spinal inputs to Gi fit CO2 and the core temperature were maintained at 4% and 37 0.5°C, poorly with reticular areas that project to the thalamus (Craig and respectively. The heart rate and blood pressure were continuously mon- Dostrovsky, 1999), and SRD neurons project primarily to the itored. The animals were mounted in a stereotaxic frame, the head being fixed in a dorsiflexed position (incisor bar elevated 10 mm above the ventromedial nucleus (Villanueva et al., 1998; Monconduit et al., standard position) (Paxinos and Watson, 1998). After surgery, the halo- 1999) but spare most of the intralaminar thalamus and noticeably thane level was reduced to 0.5–0.7%, and the mixture of nitrous oxide/ the paracentral (PC) nucleus. oxygen was maintained at 2:3–1:3 to achieve the level of anesthesia that Recently, the parabrachial internal lateral nucleus (PBil) has was adequate for ethical purposes but did not excessively depress neu- ronal responses to noxious stimuli (Benoist et al., 1984). been suggested as a possible nociceptive relay between the deep Recordings. Extracellular unit recordings were made with glass mi- spinal laminas and a part of the intralaminar thalamus that mainly cropipettes (10–15 M⍀) filled with a mixture of NaCl (5%) and Pon- project to prefrontal compartments (Fig. 1). Indeed, this nucleus tamine sky blue dye (2%). Single-unit activity and blood pressure were receives an extensive input from nociceptive neurons in laminas digitized and monitored on-line using a data acquisition system (CED 1401 with Spike 2 software; Cambridge Electronic Design, Cambridge, UK). To record neurons in the PBil, the micropipettes were inserted in Received Oct. 27, 2000; revised Dec. 27, 2000; accepted Jan. 4, 2001. the brain by using the following coordinates: 1.0–3.0 mm rostral to This work was supported by a grant from the Institut National de la Sante´etde lambda and 1.2–1.7 mm lateral to the midline. The depth was between 5.5 la Recherche Me´dicale and the Institut UPSA de la douleur (Paris, France). We thank Dr. R. Burstein for advice in the preparation of this manuscript, J. Martin for and 7.5 mm from the surface. histology, and R. Rambur for photography. Stimulation in the PC thalamic region was applied with a linear array Correspondence should be addressed to Dr. Jean-Franc¸ois Bernard, Institut of three concentric monopolar electrodes, and the distance between two National de la Sante´ et de la Recherche Me´dicale U-161, 2 rue d’Ale´sia, F-75014 adjacent center contacts of the array was 600 ␮m. The three center Paris, France. E-mail: [email protected]. contacts (100 ␮m in diameter; 150 ␮m in length) could be independently Copyright © 2001 Society for Neuroscience 0270-6474/01/212159-07$15.00/0 stimulated. The array of antidromic stimulating electrode was inserted 2160 J. Neurosci., March 15, 2001, 21(6):2159–2165 Bourgeais et al. • Internal Lateral Parabrachial Neurons and Nociception the tail, and the face using calibrated forceps, water bath, or water jet. Graded pressures (2–64 N/cm 2; exponential (ϫ2) steps; pressure surface of ϳ0.5 cm 2) or temperatures (40–52°C; ϩ2°C steps) applied in a 24 sec period were used to determine the encoding properties of the neurons. A delay of 3 min, at least, was used between successive thermal stimuli of the same part of the receptive field. Electrical square-wave stimuli (2 msec duration) were delivered through pairs of stainless steel stimulating electrodes inserted subcuta- neously into the cheeks, the paws, and the tail. The effects of the repeated application of the electrical stimulus (30 per trial, 0.66 Hz) were analyzed with the use of peristimulus histograms (PSTHs). Histological controls. In most experiments, only one unit per animal was tested. The recording sites of the 113 units antidromically identified or not were each marked by electrophoretic (5 ␮A direct current; 30 min duration; cathode in the micropipette) deposit of Pontamine sky blue at the tip of the micropipette. The location of stimulating electrodes in the thalamus nucleus were marked by iron deposit at the tip of the electrode (10-␮A direct current; 30 sec duration; anode connected to the elec- trode). At the end of the experiment, the brain was removed and fixed in a mixture of 8 vol of 1% potassium ferricyanide in 10% formalin solution added to 2 vol of 2% acetic acid in 95% alcohol solution for 3–5 d. This procedure induced the formation of Prussian blue staining at the tip of stimulating electrode. The tissue was cut in 100-␮m-thick sections and Nissl-stained. Recording and stimulating sites were determined by mi- croscopic examination and then plotted onto a series of camera lucida drawings. Data analysis. The magnitude of response was defined as the mean firing frequency during the stimulation minus the ongoing activity before the stimulation. The t test and ANOVA test were used for statistical analysis. Data are generally presented as means Ϯ SE. RESULTS The results presented below were obtained from 29 PBil neurons that were antidromically activated from the PC nucleus. The spontaneous activity of the PBil neurons was generally low; most of them (22 of 29) had a low rate of spontaneous activity (Ͻ0.5 Hz). Twenty-one neurons were located within the PBil nucleus, and eight were located within 100 ␮m from its borders (Fig. 2). Sixty-five percent of the PBil neurons were nociceptive, i.e., driven by mechanical and thermal stimuli almost only within noxious ranges, and 35% of the PBil neurons were unresponsive. All of the PBil–thalamic neurons fulfilled the criteria for anti- dromic activation (Fig. 3A–C) (see Materials and Methods). The mean latency was 8.4 Ϯ 0.8 msec (n ϭ 29; range of 2.6–20 msec) (Fig. 3F). Such latencies, with an estimated distance of 7 mm Figure 1. Schematic representation of the experimental design in rela- between the parabrachial area and the PC nucleus, indicate a slow tion to the spino–PBil–PC nociceptive pathway. A, Antidromic stimula- conduction velocity in the 0.37–2.8 m/sec range. Most low- tion delivered in the PC nucleus ( gray). AЈ, Terminal labeling in the PC nucleus from Phaseolus vulgaris leucoagglutinin (PHA-L) injection in the threshold points for antidromic activation were located in the PC PBil (modified from Bester et al., 1999). B, Unitary recording in the PBil nucleus or in its close vicinity and in the parafascicular nucleus nucleus ( gray).
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