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Intrathecal galanin potentiates the spinal analgesic effect of morphine: Behavioral and electrophysiological studies
s99 INTRATHECAL GALANIN POTENTIATES THE SPINAL ANALGESIC EFFECT OF MORPHINE: BEHAVIORAL AND ELECTROPHYSIOLOGICAL STUDIES T. Hiikfeltl, Z. Wieseu-Hall&, X-J. Xu2 and M.J. Villarl, and Clinical Neurophysiologyz, Karolinska Departments of Histology1 Stockholml and Huddingez, Sweden Institute,
RED
Mon-TIInC Hall
AIM OF INVESTIGATION: Intrathecal (i.t.) galanin (GAL), a neuropeptide widely distributed in the nervous svstem, has a complex effect on spinal flexor reflex (FR) excitability and it antagonizes the facilitatory effect of substance P (SP), calcitonin gene-related peptide (CGRP) and C-fiber strength conditioning stimulation of peripheral nerves. These results indicate that GAL may have a role in nociceptive transmission and may contribute to endogenous analgesia. We tested this hypothesis by coadministering i.t. GAL and morphine (MO) in rats. METHODS: 1.t. GAL (100 ng) was coinjected with MO (IO ng-3 pg) in two types of experiand their sensitivity to thermal with chronic i.t. catheters ments. Rats were implanted on decerebrate, spinalized, unstimuli was tested on a hot plate. In acute experiments anesthetized rats the FR was evoked by C-fiber strength electrical stimulation of the sural nerve and the effect of the drugs on the magnitude of the FR was quantified. RESULTS: GAL, which by itself had no effect on the hot plate test, potentiated the analgemect of MO. Both the magnitude and duration of the antinociceptive effect of MO were in the physiological experiments GAL, which at this dose only briefly increased. Similarly, facilitated the FR, increased the intensity and duration of the depressive effect of MO. CONCLUSIONS: The observed effects of GAL and MO on the spinal cord may involve both preand postsynaptic mechanisms. GAL may cause a subthreshold change in the excitability of dorsal horn neurons responsible for transmission of nociceptive information and thus potentiate the postsynaptic inhibitory effect of MO. These neurons may have both opiate and GAL receptors and could thus be influenced by agonists to either receptor, resulting in a synerGAL has also presynaptic inhibitory effects gistic effect when both receptors are activated. such as SP and CGRP, and, together with MO, may inhibit the release of neurotransmitters, that are believed to be involved in nociception.
NERVE SECTION ALTERS THE ANTAGONISTIC INTERACTION BETWEEN INTRATHECAL GALANIN AND OTHER NEIJROPEPTIDES ON THE FLEXOR REFLEX IN THE RAT Z. Wiesenfeld-HallinT, X-J. Xul, M.J. Villarz and T. Hokfeltz, Departments of Clinical Neurophysiologyl and Histology2, Karolinska Institute, Huddingel and Stockholm2, Sweden
Poster 150 RED Mon-Tues
_7
Exhibit
Hall
Abs
193
No
AIM OF INVESTIGATION: Neuropeptides found in somatosensory afferents have different roles in modulating the excitability of the spinal cord. The level of these peptides in dorsal root ganglion cells is altered after peripheral nerve axotomy and their effect when applied intrathecally (i.t.) is dramatically altered after sciatic nerve section (Wiesenfeld-Hallin, Brain Res., 1989, 489). The presence of galanin (GAL) in dorsal root ganglion cells is greatly increased after axotomy (Hokfelt et al., Neurosci. Lett., 1987, 83). We examined the effect of i.t. GAL on the facilitation of the nociceptive flexor reflex P (SP), calcitonin gene-related peptide (CGRP), vasoactive (FR) induced by i.t. substance intestinal polypeptide (VIP) and somatostatin (SOM) in rats with intact or unilaterally sectioned sciatic nerves. METHODS: The FR was evoked by C-fiber strength stimulation of the sural n. in decerebrate, rats with the sciatic nerve intact or sectioned 11-14 days previsp-d , unanesthetized ously. Drugs were injected on the lumbar cord surface via a PEIO catheter in a 10~1 volume. RESULTS: 1.t. SP, CGRP, VIP and SOM briefly facilitated the FR both in rats with intact GAL, at a dose which by itself facilitated the FR, applied l-4 min and sectioned nerves. prior to the other peptides significantly antagonized the facilitation induced by SP and In axotomized rats GAL antagonized CGRP, but not by VIP and SOM in rats with intact nerves. the’effects on the CGRP- and SOM-induced the facilitatory effect of VIP, but not SP, while facilitation were unchanged. CONCLUSIONS: The antagonism by GAL of C-fiber conditioning stimulus-induced facilitation 1989, 486) may be due to the SP and CGRP of the FR (Wiesenfeld-Hallin et al., Brain Res., the postsynaptic antagonistic effect of GAL in rats with intact nerves. Nerve injury alters which may reflect a change in their physlointeraction between GAL and other neuropeptides,
logical
role.
1
RED
Mon-TIInC Hall
AIM OF INVESTIGATION: Intrathecal (i.t.) galanin (GAL), a neuropeptide widely distributed in the nervous svstem, has a complex effect on spinal flexor reflex (FR) excitability and it antagonizes the facilitatory effect of substance P (SP), calcitonin gene-related peptide (CGRP) and C-fiber strength conditioning stimulation of peripheral nerves. These results indicate that GAL may have a role in nociceptive transmission and may contribute to endogenous analgesia. We tested this hypothesis by coadministering i.t. GAL and morphine (MO) in rats. METHODS: 1.t. GAL (100 ng) was coinjected with MO (IO ng-3 pg) in two types of experiand their sensitivity to thermal with chronic i.t. catheters ments. Rats were implanted on decerebrate, spinalized, unstimuli was tested on a hot plate. In acute experiments anesthetized rats the FR was evoked by C-fiber strength electrical stimulation of the sural nerve and the effect of the drugs on the magnitude of the FR was quantified. RESULTS: GAL, which by itself had no effect on the hot plate test, potentiated the analgemect of MO. Both the magnitude and duration of the antinociceptive effect of MO were in the physiological experiments GAL, which at this dose only briefly increased. Similarly, facilitated the FR, increased the intensity and duration of the depressive effect of MO. CONCLUSIONS: The observed effects of GAL and MO on the spinal cord may involve both preand postsynaptic mechanisms. GAL may cause a subthreshold change in the excitability of dorsal horn neurons responsible for transmission of nociceptive information and thus potentiate the postsynaptic inhibitory effect of MO. These neurons may have both opiate and GAL receptors and could thus be influenced by agonists to either receptor, resulting in a synerGAL has also presynaptic inhibitory effects gistic effect when both receptors are activated. such as SP and CGRP, and, together with MO, may inhibit the release of neurotransmitters, that are believed to be involved in nociception.
NERVE SECTION ALTERS THE ANTAGONISTIC INTERACTION BETWEEN INTRATHECAL GALANIN AND OTHER NEIJROPEPTIDES ON THE FLEXOR REFLEX IN THE RAT Z. Wiesenfeld-HallinT, X-J. Xul, M.J. Villarz and T. Hokfeltz, Departments of Clinical Neurophysiologyl and Histology2, Karolinska Institute, Huddingel and Stockholm2, Sweden
Poster 150 RED Mon-Tues
_7
Exhibit
Hall
Abs
193
No
AIM OF INVESTIGATION: Neuropeptides found in somatosensory afferents have different roles in modulating the excitability of the spinal cord. The level of these peptides in dorsal root ganglion cells is altered after peripheral nerve axotomy and their effect when applied intrathecally (i.t.) is dramatically altered after sciatic nerve section (Wiesenfeld-Hallin, Brain Res., 1989, 489). The presence of galanin (GAL) in dorsal root ganglion cells is greatly increased after axotomy (Hokfelt et al., Neurosci. Lett., 1987, 83). We examined the effect of i.t. GAL on the facilitation of the nociceptive flexor reflex P (SP), calcitonin gene-related peptide (CGRP), vasoactive (FR) induced by i.t. substance intestinal polypeptide (VIP) and somatostatin (SOM) in rats with intact or unilaterally sectioned sciatic nerves. METHODS: The FR was evoked by C-fiber strength stimulation of the sural n. in decerebrate, rats with the sciatic nerve intact or sectioned 11-14 days previsp-d , unanesthetized ously. Drugs were injected on the lumbar cord surface via a PEIO catheter in a 10~1 volume. RESULTS: 1.t. SP, CGRP, VIP and SOM briefly facilitated the FR both in rats with intact GAL, at a dose which by itself facilitated the FR, applied l-4 min and sectioned nerves. prior to the other peptides significantly antagonized the facilitation induced by SP and In axotomized rats GAL antagonized CGRP, but not by VIP and SOM in rats with intact nerves. the’effects on the CGRP- and SOM-induced the facilitatory effect of VIP, but not SP, while facilitation were unchanged. CONCLUSIONS: The antagonism by GAL of C-fiber conditioning stimulus-induced facilitation 1989, 486) may be due to the SP and CGRP of the FR (Wiesenfeld-Hallin et al., Brain Res., the postsynaptic antagonistic effect of GAL in rats with intact nerves. Nerve injury alters which may reflect a change in their physlointeraction between GAL and other neuropeptides,
logical
role.
1