Substance P: Transmitter O. Nociception (Minireview)
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ENDOCRINE REGULATIONS, Vol. 34,195201, 2000 195 SUBSTANCE P: TRANSMITTER O NOCICEPTION (MINIREVIEW) M. ZUBRZYCKA1, A. JANECKA2 1Department of Physiology and 2Department of General Chemistry, Institute of Physiology and Biochemistry, Medical University of Lodz, Lindleya 3, 90-131 Lodz, Poland E-mail: ajanecka@psk2.lodz.pl Substance P plays the role of a neurotransmitter immunoreactive fibers has also been detected in lam- and neuromodulator in the central and peripheral ina V of the dorsal horn (LJUNGDAHL et al. 1978), lam- nervous system. The presence of substance P in de- ina X surrounding the central canal (LAMOTTE and myelinated sensory fibres, as well as in the small SHAPIRO 1991), the nucleus dorsalis, interomediolat- and medium-sized neurons of spinal dorsal horn sub- eral cell column, and the ventral horn (PIORO et stantia gelatinosa gives a structural basis for the al.1984). Electric stimulation of the dorsal root, or hypothesis that SP plays an important role of peripheral nerve endings, causes a substantial release a mediator in the processing of nociceptive informa- of SP within the substantia gelatinosa of spinal dor- tion. In this paper recent advances on the effect of sal horns (OTSUKA and KANISHI 1976). SP on conduction and modulation of nociceptive In the dorsal regions of the spinal dorsal horn, impulsation are reviewed. The studies concerning the besides SP also large quantities of gamma-aminobu- role of SP in the prevertebral ganglia and spinal dor- tyric acid (GABA) are present, but reduction of sal horns has been presented, including the distribu- GABA levels has no effect on the SP content, and tion of SP in the spinal cord, as well as its pre- and similarly, reduction of SP levels does not cause any postsynaptic actions on excitatory and inhibitory decrease of GABA concentration in this region of postsynaptic potentials (EPSP and IPSP) and the ef- the spinal cord (TAKAHASHI and OTSUKA 1975). The fect of opiates on tachykinin transmission. above suggests that SP and GABA are localized in different spinal neurons and confirms the location 1. Distribution of substance P in the spinal cord of SP in primary afferents, while GABA is located ininhibitory interneurons (MIYATA and OTSUKA 1975). Substance P (SP) is synthesised in the spinal gan- glia, from where it is transported centrally to the sub- 2. Distribution of tachykinin receptors in the stantia gelatinosa of spinal dorsal horn and periph- spinal cord erally to the nerve endings in many tissues of the organism. SP is released at the level of the first syn- Tachykinins exert their effect by activation of spe- apse from so-called primary neurons whose perikarya cific receptors located on target cells. The distribu- are localized in the spinal ganglia in the substantia tion of tachykinin receptors in the rat spinal cord has gelatinosa of spinal dorsal horns as well as in the been examined by autoradiographic studies, which Gasserian ganglion and the trigeminal nucleus (HOE- suggest that tachykinin binding sites are located on KHELT et al. 1975; TAKAHASHI and OTSUKA 1975). postsynaptic membrane of spinal neurons (HELKE et Electron microscopy revealed that SP is highly al. 1986). Numerous diversities between the distri- concentrated in the superficial layers (lamina I-III) bution of tachykinin receptors and localisation of SP of the dorsal horn , where most primary afferent fi- immunoreactivity in the CNS have been demonstrat- bers terminate (HOEKHELT et al.1975). In other areas ed. In some cerebral regions there is a close correla- of the spinal cord a medium- or high-density of SP- tion between the density of tachykinin containing 196 MINIREVIEW SUBSTANCE P AND NOCICEPTION Table 1 Distribution of tachykinins and their receptors in the spinal cord of the rat Regions Tachykinins pmol/g Receptors SP NKA NKB NK-1 NK-2 NK-3 Substantia nigra 1154,2 115,0 2,8 Medulla oblongata 226,4 7,1 7,2 ++ Spinal cord: Dorsal horn 503,7 65,9 9,1 ++ ++++ Ventral horn 117,4 16,1 2,0 ++ fibres and density of receptors, whereas in others, been explained by its pre- or postsynaptic action (HRE- e.g. in the substantia nigra and ventral segmental DERICKSON et al. 1978). Substance P at low concen- region the correlation between these two values is trations probably stimulates the secretion of endog- not significant (MANTYH et al.1989). enous opioid peptides, and at high concentrations it The distribution of NK-3 binding sites is restrict- stimulates neuronal transmission in the nociceptive ed to the superficial dorsal horn while NK-1 binding pathways (OEHME et al. 1980). Application of SP at sites are more widely distributed in the rat spinal cord low concentration was shown to induce a dose-de- (NINKOVIC et al.1984). NK-2 binding sites were de- pendent depolarization of motoneurons in the isolat- tected in the dorsal horn (MANTYH et al.1989) (Table ed spinal cord of the newborn rat, as recorded extra- 1), whereas NK-2 receptor mRNA was undetectable cellularly from the ventral root or intracellularly from in the rat spinal cord (TSUCHIDA et al.1990), but it motoneurons (KONISHI and OTSUKA 1974). This SP- was detected in the sensory ganglia or in peripheral induced depolarization is predominantly due to inflammed tissues reached by IR-SP. It was also dem- a transsynaptic action through interneurons, since it onstrated that the level of NK-1 receptor mRNA was is largely blocked by tetradoxin (OTSUKA and YANAG- elevated in the tissues affected by inflammation, ISAWA 1980; YANAGISAWA and OTSUKA 1990). which indicates that the flexibility of expression of Ionophoretic application of SP produces NK-1 receptor gene may regulate the sensitivity to a prolonged depolarization of dorsal horn neurons SP in a way similar to that observed in the spinal in the spinal cord in vivo (HENRY 1976) and in cul- dorsal horn (MC CARSON 1999). No significant cor- tured spinal neurons (NOWAK et al. 1982). Studies relation between the distribution of tachykinins and with spinal cord slices of young rats by URBAN and their receptors in the CNS was found. Moreover, it RANDIC (1984) showed that both the application of has been suggested that the binding sites of labelled SP and electrical stimulation of a dorsal root induced tachykinins in autoradiography reflect the receptor a slow depolarization of dorsal horn cells as record- binding sites of high affinity, whereas those with low ed intracellulary. Both the SP-induced and the elec- affinity remain undetected, although they play an trical stimulus-induced depolarizations were blocked important physiological role (STROES and BAST 1986). by tachykinin antagonists or SP antibodies. 3. Effects of stimulation of primary afferents on 4. Role of substance P in nociceptive substance P release transmission Effect of SP on nociception depends on its con- It is believed that SP together with other tachyki- centration. Intraventricular or intraperitoneal admin- nins is responsible for nociceptive transmission from istration of low concentrations of SP exerts analge- the peripheral to the central nervous system (IVERS- sic effect (STEWART et al. 1976), whereas in high con- EN 1982). The structural basis for such hypothesis is centrations it may induce hyperalgesia which has the fact that SP occurs in small and medium-sized MINIREVIEW SUBSTANCE P AND NOCICEPTION 197 neurons of substantia gelatinosa of the spinal dorsal A suitable model to investigate slow SP-induced horn, as well as in peripheral and central endings of EPSP is the inferior mesenteric ganglion of the guinea primary afferent fibres. Among primary afferent fi- pig. Brief pulse application of SP induces a slow bers, unmyelinated C-fibers are known to convey depolarization lasting tens of seconds in cultured delayed pain to second-order neurons in the superfi- spinal neurons (NOWAK and MACDONALD 1982). Ap- cial dorsal horn of spinal cord and medulla oblonga- plication of SP at low concentrations produced ta. In rats C-fibers constitute of about 70 % of nerve a depolarization of inferior mesenteric ganglion cells fibers and 83 % of saphenous nerve fibers (NAGY of the guinea pig (KONISHI and OTSUKA 1985). When and Van der KOOY 1983). In rats, 80 % of C-fibers the potential was recorded intracellulary from gan- are polymodal nociceptors (LYNN and HUNT 1984). glion cells, stimulation with a single or repetitive It seems likely, therefore, that most SP-immunore- shocks of the lumbar splanchnic nerves induced fast active C-fibers belong to polymodal nociceptors. cholinergic EPSPs followed by a noncholinergic slow Intrathecal injection of SP in mice elicits the behav- EPSPs (TSUNOO et al. 1982). Upon stimulation of ior suggesting the pain sensation (HYLDEN and WIL- dorsal roots, a slow EPSP was evoked in ganglion COX 1981), whereas tachykinin antagonists (LEMBECK cells that was not accompanied by fast EPSPs (KON- et al. 1981; ZUBRZYCKA et al. 1997) or SP antibody ISHI et al. 1980). Slow EPSP and the depolarization (KURAISHI and SATAH 1990) administered by the same induced by short pulse application of SP have route produce an analgesic effect. Intrathecal injec- a similar time course of 30 s to a few minutes and tion of SP in rats also facilitates a spinal nociceptive are associated with a similar conductance change reflex (YASHPAL and HENRY 1983). WIESENHELD-HAL- (TSUNOO et al. 1982). Both, the slow EPSP and the LIN (1986) found that intrathecally injected SP as well SP-induced depolarization are blocked by tachyki- as C-afferent stimulation increased the magnitude of nin antagonists and augmented by isoprenalin (KON- the spinal flexion reflex elicited by noxious mechan- ISHI and OTSUKA 1985). During a prolonged applica- ical or thermal stimuli in the rat and thus sugested tion of SP, witch produces a sustained depolariza- that SP may be released from polymodal nocicep- tion of ganglion cells, the slow EPSP is obliterated.