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Heterogeneous Distribution of Neurotensin-Like Lmmunoreactive Neurons and Fibers in the Midbrain Periaqueductal Gray of the Rat

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Heterogeneous Distribution of Neurotensin-Like Lmmunoreactive Neurons and Fibers in the Midbrain Periaqueductal Gray of the Rat The Journal of Neuroscience, July 1987, 7(7): 2025-2034 Heterogeneous Distribution of Neurotensin-like lmmunoreactive Neurons and Fibers in the Midbrain Periaqueductal Gray of the Rat Michael T. Shipley,1,2 John H. McLean,’ and Michael M. Behbehani3 ‘Department of Anatomy and Cell Biology, Division of Neurobiology, ‘Department of Neurosurgery, and 3Department of Physiology and Biophysics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0521 The midbrain periaqueductal gray (PAG) has been shown to et al., 1976, 1978; Basbaum and Fields, 1979) and modulate be a site where various manipulations induce pain suppres- local spinal nociceptive circuits (Basbaum and Fields, 1984). sion. Recent physiological evidence (Behbehani and Pert, Thus, lesions of NRM and its surrounding area block or atten- 1984; Behbehani et al., 1987) suggests that neurotensin has uate all known forms of PAG-induced analgesia(Behbehani and pronounced physiological actions in PAG and effects pain Fields, 1979; Behbehani and Pert, 1984; Sandkuhler and Geb- suppression. We have performed immunohistochemical hart, 1984) and naloxone blocks the analgesiainduced by mor- studies in order to determine the magnitude and distribution phine injections in PAG. of neurotensin-like immunoreactive (NT-IR) cell bodies and Several studieshave demonstratedthat central administration fibers in PAG. NT-IR cell bodies were common throughout of the tridecapeptide neurotensin (NT) produces a significant PAG, although there were more in the caudal than the rostra1 long-lastinganalgesia (Clineschmidt and McGuffin, 1977; Nem- half. NT-IR neurons were much more numerous in the ventral eroff et al., 1979; Kalivas et al., 1982). Recently, Behbehani and than the dorsal half of PAG, and some appeared to be located Pert (1984) showed that NT injected in PAG caused pain within the dorsal raphe nucleus. The pattern of NT-IR fibers suppressionthat wasas potent asthat induced by similar amounts was analyzed with the aid of image enhancement/analysis of morphine. These investigators elucidated several key features and densitometry. The fibers were found to be heteroge- of the NT effect: (1) Local application of NT causedlong-lasting neously distributed, being most heavily concentrated in the excitation of PAG neurons; (2) injection of NT in PAG increased region adjacent to the cerebral aqueduct in the caudal two- the firing rate of NRM neurons having identified projections to thirds of PAG. The distribution of NT fibers closely matches the spinal cord; (3) lesions of NRM abolished the antinocicep- sites where exogenously applied NT elicits long-lasting ex- tive action produced by injection of NT in PAG. Thus, it was citation of PAG neurons (Behbehani et al., 1987). Based on hypothesized that NT acted upon neuronsin PAG that, in turn, the known physiological and behavioral actions of NT in PAG, activated neurons in NRM ventral medullary area whose pro- the present anatomical results suggest that NT acts on ele- jection to the spinal cord is necessary for all known central ments located predominantly in the medial and ventrolateral antinociceptive effects. parts of PAG. Neurons activated by NT may project directly Significantly, this NT-activated antinociceptive mechanism, to the nucleus raphe magnus and adjacent ventral medulla unlike the morphine effect, is not blocked by naloxone. Thus, (Behbehani and Pert, 1984) to activate neurons that project it would appear that the action of NT is mediated by the same to the spinal cord and modulate nociceptive circuits. PAG-NRM-spinal cord pathways as morphine but operates through different groups of neurons or different postsynaptic It is well established that stimulation of the midbrain peri- receptor populations. Therefore, it is important to define the aqueductal gray (PAG) activates circuits that project to the spin- neural substratesof NT’s action in PAG, as it appearsto involve al cord and mediate pain suppression.This phenomenon can a parallel but independent mechanism to the opiate channel. be initiated by electrical stimulation (Reynolds, 1969) or local The existence of NT in PAG has been establishedby im- application of the excitatory amino acid glutamate (Behbehani munohistochemical methods (Uhl and Snyder, 1976; Koba- and Fields, 1979). Injection of morphine in PAG also causes yashi et al., 1977; Beitz, 1982b; Jenneset al., 1982) and the in long-lasting analgesia,which is blocked by the opiate antagonist vitro binding of tritiated NT in PAG has been demonstrated naloxone (Yaksh et al., 1976). These manipulations appear to and interpreted as evidence of the presenceof NT receptor sites engagecircuits in PAG that project to the nucleusraphe magnus (Lazarus et al., 1977; Young and Kuhar, 1981; Quirion et al., (NRM) and adjacent ventral medullary region and activate neu- 1982). However, these previous reports provide little infor- rons that project to the dorsal horn of the spinal cord (Basbaum mation about the topological organization of neurotensinergic elements in PAG. The present study was undertaken to close this gap by characterizing the distribution of NT-immunoreac- Received May 28, 1986; revised Sept. 23, 1986; accepted Oct. 30, 1986. We wish to thank Sharon Harding for typing the manuscript and B. Frydel, M. tive (IR) neurons and fibers in PAG. The results indicate that Clements, and K. Wilbum for technical assistance. We also wish to thank Dr. NT fibers have a markedly heterogeneousdistribution in PAG. Alvin Beitz for his helpful suggestions for optimizing the colchicine concentrations to visualize NT cell bodies. This work was supported by Grants DAMD 17-86- Materials and Methods C-6005, NS-20643, and NS-23348. Correspondence should be addressed to Dr. Michael T. Shipley at the above Adult, maleSprague-Dawley rats (Harlanand Zivic-Miller) wereused. address. The animalswere deeply anesthetized with sodiumpentobarbital and Copyright 0 1987 Society for Neuroscience 0270-6474/87/072025-10$02.00/O transcardiallyperfused. Following a brief clearingrinse with normal 2026 Shipley et al. - Neurotensin in PAG saline, the animals were perfused for 30 min with 4% paraformaldehyde Thus, as will be described below, different parts of PAG character- in sodium phosphate buffer (PB). The brains were removed, postfixed istically have different densities of NT-IR staining. The function of the for 30 min to 5 hr, and then placed in 20% sucrose-PB on a shaker isodensitometry program is to calculate the gray levels (O-63) (staining table in a cold room (4°C) overnight. Frozen sections (30 Frn thick) were intensities) of each of the 5 12 x 5 12 points in the digitized image and collected in cold PBS, rinsed (2 x 10 min), and transferred to PBS convert the distribution of gray values to a density scale (0.0-l .O). The containing 2% normal goat serum (NGS) and 0.3% Triton X-100 for program then draws closed boundary lines around contiguous regions 45 min. Following a PBS rinse (2 x 10 min), the sections were incubated of equal density (isodensity contours). Since the range ofdensities within overnight at 4°C in rabbit anti-NT antisera (Immuno Nuclear, Inc.; any local region may fluctuate somewhat because of the discrete nature diluted 1:500) in PBS containing 2% NGS and 0.3% T&on. The sections of the stain, it is useful to lump densities within certain ranges together, were then rinsed (2 x 10 min PBS) and incubated for 45 min in bio- and the program allows the user to specify the number and cut-off points tinylated goat anti-rabbit IgG (Vector Lab) in PBS containing 2% NGS of these isodensity regions. The program then delineates, using different and 0.3% Triton. Following 2 rinses (2 x 10 min PBS), the sections colored binary overlay lines, the boundaries of the regions whose den- were incubated in avidin-biotin complex (ABC) (Vector Lab) in PBS sities fall within specified ranges. A recursive procedure identifies low- containing 2% NGS. Usually, the biotinylated IgG-rinse-ABC cycle was density regions surrounded by higher-density regions so that “holes in repeated a second time. After the ABC step the sections were rinsed the donut” are detected. The result of these operations is to delineate (2-x 10 min) in phosphate buffer and then incubated in a solution regions of isodensity in the image. The user may then use different containing 0.05% diaminobenzidine and 0.0 1% H,O, in phosphate buff- conventions (solid filling, dots of different spacing, etc.) to indicate er for 5-20 min. The DAB reaction was stopped in 3^rinses (10 min different regions of isodensity so that the information can be reduced each) of phosphate buffer and mounted onto gelatinized slides. to a black-and-white schematic. The numerical value of the average In most cases, the staining was intensified by first defatting the mount- density for each isodensity region can also be represented in the graphic ed sections in a graded series of ethyl alcohol, followed by rehydration printout. By using the same density cut-off values and illumination and a brief (l-2 min) reaction with 1% osmium tetroxide. The sections conditions and by controlling for unacceptable variations in section were then cleared and coverslipped with Permount. thickness, successive sections can be analyzed to generate isodensity Immunohistochemical controls were performed by incubating some maps for a series of sections. sections with the primary antibody omitted or with the primary anti- The same qualifications stated for the color density maps apply to body preabsorbed by an excess of NT (Immuno Nuclear, Inc.; 50 llg/ the isodensitometric analysis. Thus, the density readings have no simple ml of diluted antisera). In no case was immunocytochemical staining relationship to the amount of NT present in the measured regions, observed in the PAG control sections. although the ratiosof densities in different regions do reflect the relative Cell body versusfiber staining. During the course of this study, it distribution of the peptide within the limits of sensitivity of immuno- became clear that different procedures were required for optimal staining histochemistry.
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