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Enkephalin and Substance P

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Enkephalin and Substance P Proc. Nati. Acad. Scf. USA Vol. 74, No. 7, pp. 3081-3085, July 1977 Neurobiology Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: Enkephalin and substance P (spinal interneurons/descending spinal systems/primary afferents) TOMAS HOKFELT*, AKE LJUNGDAHL*, LARS TERENIUSt, ROBERT ELDE**, AND GORAN NILSSON§ Departments of * Histology and § Pharmacology, Karolinska Institute, Stockholm, and t Department of Medical Pharmacology, Uppsala University, Uppsala, Sweden Communicated by U. S. von Euler, April 25,1977 ABSTRACT The distribution of Met-enkephalin- and sub- in morphine- and stimulation-produced analgesia: the peri- stance P-immunoreactive neurons was studied by indirect im- aqueductal central gray, the medullary raphe nuclei, the spinal munofluorescence in some areas related to pain and analgesia. Met-enkephalin- and substance P-positive cell bodies and nerve trigeminal nucleus, and the spinal cord. It may be significant terminals were observed in the periaqueductal central gray, the that another peptide, substance P, originally discovered by von nucleus raphe magnus, the marginal layer and substantia ge- Euler and Gaddum (23) and structurally characterized by latinosa ofthe spinal trigeminal nucleus, and the dorsal horn Leeman and collaborators (24), is present in the same or adja- of the spinal cord. Lesion experiments suggest that Met-en- cent areas and also in a population of primary sensory neurons kephalin neurons in the dorsal horn and possibly in the spinal (25). In the present paper, the immunohistochemical distri- trigeminal nucleus are interneurons or propriospinal neurons bution of the and substance P systems is compared with nerve terminals in the laminae I and II of tfe cord and in enkephalin the superficial layers of the spinal trigeminal nucleus, respec- with neural substrates involved in pain and analgesia (see refs. tively. These areas are also very rich in substance P-positive 10 and 26). nerve terminals, mainly representing central branches of pri- mary afferent neurons. The present immunohistochemical-anatomical findings MATERIAL AND METHODS support the hypothesis that stimulation-produced analgesia is related to activation of spinal and spinal trigeminal enkephalin Male albino rats (Sprague-Dawley, body weight 150 g) were interneurons forming axo-axonic synapses with (substance P?) divided into three groups: (i) untreated rats, (ii) rats receiving pain afferents in the superficial laminae of the dorsal horn and an injection of 10 or 25 pug of colchicine dissolved in 0.9% the spinal trigeminal nucleus. These interneurons may be acti- (wt/vol) saline (1 gug//l) into the lateral ventricle or the cisterna vated by sensory fibers and by descending fibers from medullary 20 stimulation sites. Transmitter substances in these descending magna, and (iii) rats receiving an intraspinal injection of ,ug fibers may be 5-hydroxytryptamine and substance P. of colchicine dissolved in 0.9% saline (10 ,ug!/ul) at the lumbo- sacral level. The colchicine-treated animals were sacrificed Morphine is a classical agent for the relief of severe, chronic 24-48 hr after the injection. pain. Strong analgesia can also be produced by electric stimu- We have previously observed widespread enkephalin-posi- lation of mesencephalic and medullary structures (refs. 1-9, see tive nerve terminals whereas no immunoreactive cell bodies ref. 10), by acupuncture, or by "electroacupuncture" (11, 12), could be detected (20). Colchicine has been used in other studies a modification of the classical Chinese procedure. Several ob- to increase cell body levels of catecholamines (27), probably due servations suggest a common element in these approaches for to inhibition of axonal transport. pain relief. For instance, narcotic antagonists, such as naloxone Antiserum to Met-enkephalin was raised in rabbits as de- (13), block analgesia induced by electrical stimulation (6-9, 14) scribed elsewhere (20). Crossreaction was about 10% with and by morphine injections (15). Furthermore, tolerance de- Leu-enkephalin and <0.1% with a-, A-, and 'y-endorphins, velops to electrostimulation analgesia and to morphine analgesia substance P, and somatostatin (L. Terenius, unpublished re- and cross tolerance can be observed (16). suIts). Furthermore, because Met-enkephalin occurs in amounts Recently, Hughes and collaborators (17) have identified two 3-4 times greater than those of Leu-enkephalin in rat brain (28), pentapeptides, Leu-enkephalin and Met-enkephalin, that may we ascribe most of the immunofluorescence to Met-enkephalin. represent endogenous ligands for opiate receptors. Available Antiserum against substance P was raised in rabbits as described evidence suggests that the activity profile of endogenous opioids previously (29). is similar to that of the opiates. For instance, enkephalin has The rats were perfused with formalin. After being rinsed, analgesic activity in vivo and the narcotic antagonist naloxone the brain and spinal cord were cut on a cryostat (Dittes, will also counteract enkephalin-induced elevation of pain Heidelberg) and processed for the indirect immunofluorescence thresholds (18, 19). It is therefore conceivable that these ligands technique (see ref. 30). Series of four consecutive sections at may be involved in stimulation-produced analgesia. different levels of the mesencephalon, lower brain stem, and Using the immunohistochemical approach, we have been spinal cord were incubated for 30 min in a humid atmosphere able to outline the gross distribution of enkephalin-positive at 370 with antiserum to Met-enkephalin (diluted 1:10 or 1:20), structures in the central nervous system (refs. 20 and 21, see also substance P (diluted 1:40), and the two control sera, respec- ref. 22). Enkephalin neurons were found in many areas of the tively. The control sera, in which the Met-enkephalin and brain and spinal cord, indicating involvement in many different substance P antibodies were blocked with the respective peptide types of central nervous system functions. Here, however, we (50 jug/ml of serum diluted 1:10), were included to establish focus attention strictly on areas assumed to be of importance the specificity of the staining. After a rinse in phosphate-buf- fered saline, the sections were incubated with fluorescein iso- * Present address: Department of Anatomy, University of Minnesota, thiocyanate-conjugated antibodies (SBL, Stockholm; diluted Minneapolis, MN. 1:4) under the same conditions as described above, rinsed in 3081 Downloaded by guest on September 29, 2021 3082 Neurobiology: Hokfelt et al. Proc. Natl. Acad. Sci. USA 74 (1977) 1^~~~i FIG. 1. Immunofluorescence studies. Arrowhead always points dorsally. DF, dorsal funiculus; P, tractus corticospinalis; asterisk indicates central canal. (Bar indicates 50Mm.) Anatomic sites: dorsal horn ofthe spinal cord (A, B); nucleus raphe magnus (C); intermediate gray matter of the sacral spinal cord (D-F). Treatments: untreated (A, B); colchicine-treated (C-F). Sera: antiserum to substance P (A, C, E); antiserum to Met-enkephalin (B, D); enkephalin control serum (F). A and B and D, E, and F are consecutive sections, respectively. A high density ofsubstance P-positive nerve terminals was seen in laminae I and II of the dorsal horn (A). The rectangle in A indicates approximately the area shown in B. The enkephalin-positive nerve terminals had a parallel but less dense distribution as seen at the higher magnification (B). Note lack of en- kephalin-positive fibers in the zone of Lissauer (arrow in B) whereas numerous substance P-positive fibers are present in this area (arrow in A). Numerous substance P-immunoreactive cell bodies were seen in the nucleus raphe magnus (C) after colchicine treatment. At the sacral level both enkephalin- (arrows in D) and substance P-positive (arrows in E) cell bodies were seen after intraspinal colchicine injections. Note the networks ofenkephalin- (D) and substance P-positive (E) nerve terminals. No fluorescent neurons or nerve terminals were seen after incubation with control serum (F). phosphate-buffered saline, mounted in phosphate-buffered RESULTS saline/glycerol, 1:3 (vol/vol), and examined in a Zeiss fluores- In untreated rats, extensive networks of Met-enkephalin- and cence microscope. The anatomical nomenclature is according substance P-positive nerve terminals were observed in the to Palkovits and Jacobowitz (31). periaqueductal central gray and in the marginal layer and Downloaded by guest on September 29, 2021 Neurobiology: Hakfelt et al. Proc. Natl. Acad. Sci. USA 74 (1977) 3083 I 16 FIG. 2. Immunofluorescence studies of the dorsal horn of the spinal cord (lower lumbar and upper sacral level) of colchicine-treated rat after incubation with antiserum to Met-enkephalin. DF, dorsal funiculus. (Bar indicates 50 Am.) Cell bodies (arrows) are observed in superficial (B) and deeper laminae (C). B and C represent higher magnifications ofA as indicated by rectangles. Note that the fluorescent nerve terminals are less bright compared to Fig. 1B. substantia gelatinosa of the spinal trigeminal nucleus. It is im- observed. The results described above are summarized in Fig. portant to note that both enkephalin- and substance P-positive 3. fibers were present only in the caudal parts of the spinal tri- Met-enkephalin- and substance P-positive cell bodies, axons, geminal nucleus and that there was a striking overlap between and nerve terminals were observed also in many other areas of the distribution patterns of the nerve terminals
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