- Email: [email protected]
Interactions of galanin and morphine in the spinal antinociception in rats with mononeuropathy
Brain Research 852 Ž2000. 485–487 www.elsevier.comrlocaterbres
Short communication
Interactions of galanin and morphine in the spinal antinociception in rats with mononeuropathy Yan-Ping Zhang a , Thomas Lundeberg b , Long-Chuan Yu a
a, )
Department of Physiology and National Laboratory of Biomembrane and Membrane Biotechnology, College of Life Science, Peking UniÕersity, Beijing 100871, China b Department of Physiology and Pharmacology, Department of Surgery and Rehabilitation, Karolinska Institutet, 171 77 Stockholm, Sweden Accepted 12 October 1999
Abstract The increased hind-paw withdrawal latency ŽHWL. to thermal stimulation and hind-paw withdrawal threshold ŽHWT. to mechanical stimulation induced by morphine were attenuated by intrathecal injection of 1 or 3 nmol, but not 0.3 nmol of the selective galanin antagonist galantide. The result indicated a possible interaction between galanin and opioids in the transmission of presumed nociceptive information in the spinal cord of rats with mononeuropathy. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Galanin; Opioid; Galantide; Nociceptive test; Mononeuropathy
The role of galanin in nociception has attracted much interest. In intact rats, the spinal antinociception induced by morphine was antagonized by galanin receptor antagonists w5x. It is suggested that galanin and morphine interact at the spinal cord level in the modulation of presumed nociceptive information. This suggestion is supported by the results that the antinociceptive effects of opioids in the spinal cord can be enhanced and prolonged by the co-administration of galanin w3,6x. Recent study in our laboratory have demonstrated that exogenous galanin increased the latency to hind-paw withdrawal both to noxious thermal and mechanical stimulation in rats with mononeuropathy w9x. In the present study we set out to elucidate the interaction between galanin and morphine in the spinal antinociception in rats with mononeuropathy. Adult male Sprague–Dawley rats ŽExperimental Animal Center of Beijing Medical University, Beijing, China. were used. All experiments were conducted according to the guidelines of the Animal Ethical Committee of Karolinska Institutet. Rats were anesthetized with i.p. sodium pentobarbital Ž45 mgrkg.. In order to create a mononeuropathy model, nerve ligation was performed according to Bennett and Xie w2x. An intrathecal catheter was
)
Corresponding [email protected]
author.
Fax:
q 86-106-275-1850;
e-mail:
implanted in each rat immediately following nerve ligation. A sterilized saline flushed polyethylene ŽPE-10. tube was inserted into the subarachnoid space through a slit in the atlanto-occipital membrane. The caudal end of the catheter was gently threaded into the lumbar enlargement. The rats exhibiting post-surgical motor deficits Že.g., limb paralysis. were excluded from the experiment. Intrathecal administrations were performed during 5–12 days after left sciatic nerve ligation when the abnormal pain behavior was almost at a stable maximum w1,2,9x. The hind-paw withdrawal latency ŽHWL. in seconds to thermal stimulation and the hind-paw withdrawal threshold ŽHWT. in grams to mechanical stimulation were measured. The thermal response was assessed using the hot-plate test. The rat’s left or right hind-paw was separately placed manually on the hot-plate which was maintained at a temperature of 528C Ž51.8–52.48C. w8,9x. The time of hind-paw withdrawal was measured. The response to mechanical stimulus was determined by the Randall Selitto Test ŽUgo Basile, Type 7200, Italy.. A wedge-shaped pusher at a loading rate of 30 grs was applied to the dorsal surface of the hind-paw and the threshold required to initiate the struggle response was measured. The values obtained before intrathecal injection were regarded as the basal HWL or HWT. The HWL and HWT recorded during subsequent experiments were expressed as percentage change of the mean basal level for each rat Žpercent change of HWL or HWT.. Each rat was tested with both nociceptive tests.
0006-8993r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 2 2 3 6 - 2
486
Y.-P. Zhang et al.r Brain Research 852 (2000) 485–487
Fig. 1. Effects of intrathecal injection of galantide on the morphine-induced increase in HWL and HWT in mononeuropathic rats. ŽA. Left HWL; ŽB. right HWL; ŽC. left HWT; ŽD. right HWT. Time s 0 min: 26.6 nmol of morphine was administered intrathecally; Time s 10 min: intrathecal administration of 0.3, 1 or 3 nmol of galantide or 10 ml of 0.9% saline as the control. Number of rats in each group: n s 9. Vertical bars indicate S.E.M., two-way ANOVA, U P - 0.05, UU P - 0.01 and UUU P - 0.001 compared with the control group. HWL: hind-paw withdrawal latency, HWT: hind-paw withdrawal threshold.
Data from nociceptive tests were presented as mean " S.E.M. with n s 9 per group. The difference between groups was determined by two-way analysis of variance ŽANOVA., U P - 0.05, UU P - 0.01 and UUU P - 0.001 were considered as significant. The notation of Fleftrleft , Fleftrright or Frightrright expresses the F-value in ANOVA, and left or right means left HWL Žor HWT. or right HWL Žor HWT.. Solutions for intrathecal administration were prepared with sterilized saline, each with a volume of 10 ml: Ž1. 26.6 nmol of morphine ŽMorphine Hydrochloride, Shenyang First Pharmaceutical Factory, China.; Ž2. 0.3, 1, or 3 nmol of galantide Žgalantide: galanin-Ž1–12.-pro-substance P-Ž5–11., Bachem, Feinchemikalien, Switzerland.. Control groups were given 10 ml of 0.9% saline. Thirty-six rats with mononeuropathy were divided into four groups receiving intrathecal injections of 26.6 nmol of morphine, followed 10 min later by: 0.3, 1 or 3 nmol of galantide or 10 ml of 0.9% saline as a control. The results are shown in Fig. 1. After the injection of morphine, the HWL and HWT increased in all four groups. Twenty minutes after intrathecal injection of galantide, the increased HWL and HWT were attenuated significantly in the groups of receiving 3 nmol Žhot-plate test: Fleftrleft s 9.49, P - 0.01; Frightrright s 14.32, P - 0.001. Randall Selitto test: Fleftrleft s 6.87, P - 0.05; Frightrright s 15.79, P - 0.001. and 1 nmol of galantide Žhot-plate test: Frightrright s 9.20, P - 0.01. Randall Selitto test: Fleftrleft s 4.52, P - 0.05; Frightrright s 18.20, P - 0.001. compared with the control group, with the exception of the hot-plate test in the left hind-paw Ž Fleftrleft s 2.05, P s 0.16.. In the group receiving 0.3 nmol of galantide, there were no significant changes compared with the control group.
The present results showed that the increased HWL and HWT induced by morphine were attenuated by intrathecal injection of 1 or 3 nmol of galantide, suggesting there is an interaction between galanin and opioids in mononeuropathy. The results are supported by the report in which galanin acted synergically with opioids to suppress the nociceptive flexor reflex in the spinal flexor reflex model w6x. Also, Reimann et al. w4x reported that the spinal antinociception elicited by morphine was antagonized by two types of galanin receptor antagonists, galantide and M35 Žgalanin-Ž1–13.-bradykikin-Ž2–9.-amid. in rats with inflammation. Similar findings were obtained by Selve et al. w5x who reported that galantide co-administered intrathecally with other antinociceptive drugs Žfor example, tramadol, wD-Ala-NMePhe-Gly-olx-enkephalin, DAMGO. reduced their antinociceptive effects. Recent study of our laboratory showed that the increased nociceptive response latencies induced by intra-periaqueductal grey injection of galanin was reversed by naloxone w7x. Taken together, it is possible that galanin as neuropeptide involved in the antinociception acts synergically with opioids to inhibit the nociceptive information transmission.
Acknowledgements This study was supported by the funds from Karolinska Institutet Foundation, Foundation for Acupuncture and Alternative Treatment Methods and National Natural Science Foundation of China ŽNSFC. and the Natural Science Research Foundation of Peking University.
Y.-P. Zhang et al.r Brain Research 852 (2000) 485–487
References w1x N. Attal, F. Jazat, V. Kayser, G. Guibaud, Further evidence for a ‘pain related’ behaviour in a model of unilateral peripheral mononeuropathy, Pain 41 Ž1990. 235–251. w2x G.J. Bennett, Y.K. Xie, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain 33 Ž1988. 87–107. w3x B. Przewlocka, H. Machelska, P. Rekowski, G. Kupryszewski, R. Przewlocki, Intracerebroventricular galanin and N-terminal galanin fragment enhance the morphine-induced analgesia in the rat, J. Neural Transm. 102 Ž1995. 229–235. w4x W. Reimann, W. Englberger, E. Friderichs, N. Selve, B. Wilffert, Spinal antinociception by morphine in rats is antagonized by galanin receptor antagonists, Naunyn-Schmiedeberg’s Arch. Pharmacol. 350 Ž1994. 380–386.
487
w5x N. Selve, W. Englberger, E. Friderichs, H. Hennies, W. Reimann, B. Wilffert, Galanin receptor antagonists attenuate spinal antinociceptive effects of DAMGO, tramadol and non-opioid drugs in rats, Brain Res. 735 Ž1996. 177–187. w6x Z. Wiesenfeld-Hallin, X.J. Xu, M.J. Villar, T. Hokfelt, Intrathecal galanin potentiates the spinal analgesic effect of morphine: electrophysiological and behavioral studies, Neurosci. Lett. 109 Ž1990. 217–221. w7x D. Wang, H.H. Ye, L.C. Yu, T. Lundeberg, Intra-periaqueductal grey injection of galanin increases the nociceptive response latency in rats, an effect reversed by naloxone, Brain Res. 834 Ž1999. 152–154. w8x T.L. Yaksh, A.B. Malmberg, Central pharmacology of nociceptive transmission, in: P.D. Wall, R. Melzack ŽEds.., Textbook of Pain, 3rd edn. Churchill Livingstone, Edinburgh, 1994, pp. 165–200. w9x L.C. Yu, T. Lundeberg, H. An, F.X. Wang, T. Lundeberg, Effects of intrathecal galanin on nociceptive responses in rats with mononeuropathy, Life Sci. 64 Ž1999. 1145–1153.
Short communication
Interactions of galanin and morphine in the spinal antinociception in rats with mononeuropathy Yan-Ping Zhang a , Thomas Lundeberg b , Long-Chuan Yu a
a, )
Department of Physiology and National Laboratory of Biomembrane and Membrane Biotechnology, College of Life Science, Peking UniÕersity, Beijing 100871, China b Department of Physiology and Pharmacology, Department of Surgery and Rehabilitation, Karolinska Institutet, 171 77 Stockholm, Sweden Accepted 12 October 1999
Abstract The increased hind-paw withdrawal latency ŽHWL. to thermal stimulation and hind-paw withdrawal threshold ŽHWT. to mechanical stimulation induced by morphine were attenuated by intrathecal injection of 1 or 3 nmol, but not 0.3 nmol of the selective galanin antagonist galantide. The result indicated a possible interaction between galanin and opioids in the transmission of presumed nociceptive information in the spinal cord of rats with mononeuropathy. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Galanin; Opioid; Galantide; Nociceptive test; Mononeuropathy
The role of galanin in nociception has attracted much interest. In intact rats, the spinal antinociception induced by morphine was antagonized by galanin receptor antagonists w5x. It is suggested that galanin and morphine interact at the spinal cord level in the modulation of presumed nociceptive information. This suggestion is supported by the results that the antinociceptive effects of opioids in the spinal cord can be enhanced and prolonged by the co-administration of galanin w3,6x. Recent study in our laboratory have demonstrated that exogenous galanin increased the latency to hind-paw withdrawal both to noxious thermal and mechanical stimulation in rats with mononeuropathy w9x. In the present study we set out to elucidate the interaction between galanin and morphine in the spinal antinociception in rats with mononeuropathy. Adult male Sprague–Dawley rats ŽExperimental Animal Center of Beijing Medical University, Beijing, China. were used. All experiments were conducted according to the guidelines of the Animal Ethical Committee of Karolinska Institutet. Rats were anesthetized with i.p. sodium pentobarbital Ž45 mgrkg.. In order to create a mononeuropathy model, nerve ligation was performed according to Bennett and Xie w2x. An intrathecal catheter was
)
Corresponding [email protected]
author.
Fax:
q 86-106-275-1850;
e-mail:
implanted in each rat immediately following nerve ligation. A sterilized saline flushed polyethylene ŽPE-10. tube was inserted into the subarachnoid space through a slit in the atlanto-occipital membrane. The caudal end of the catheter was gently threaded into the lumbar enlargement. The rats exhibiting post-surgical motor deficits Že.g., limb paralysis. were excluded from the experiment. Intrathecal administrations were performed during 5–12 days after left sciatic nerve ligation when the abnormal pain behavior was almost at a stable maximum w1,2,9x. The hind-paw withdrawal latency ŽHWL. in seconds to thermal stimulation and the hind-paw withdrawal threshold ŽHWT. in grams to mechanical stimulation were measured. The thermal response was assessed using the hot-plate test. The rat’s left or right hind-paw was separately placed manually on the hot-plate which was maintained at a temperature of 528C Ž51.8–52.48C. w8,9x. The time of hind-paw withdrawal was measured. The response to mechanical stimulus was determined by the Randall Selitto Test ŽUgo Basile, Type 7200, Italy.. A wedge-shaped pusher at a loading rate of 30 grs was applied to the dorsal surface of the hind-paw and the threshold required to initiate the struggle response was measured. The values obtained before intrathecal injection were regarded as the basal HWL or HWT. The HWL and HWT recorded during subsequent experiments were expressed as percentage change of the mean basal level for each rat Žpercent change of HWL or HWT.. Each rat was tested with both nociceptive tests.
0006-8993r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 2 2 3 6 - 2
486
Y.-P. Zhang et al.r Brain Research 852 (2000) 485–487
Fig. 1. Effects of intrathecal injection of galantide on the morphine-induced increase in HWL and HWT in mononeuropathic rats. ŽA. Left HWL; ŽB. right HWL; ŽC. left HWT; ŽD. right HWT. Time s 0 min: 26.6 nmol of morphine was administered intrathecally; Time s 10 min: intrathecal administration of 0.3, 1 or 3 nmol of galantide or 10 ml of 0.9% saline as the control. Number of rats in each group: n s 9. Vertical bars indicate S.E.M., two-way ANOVA, U P - 0.05, UU P - 0.01 and UUU P - 0.001 compared with the control group. HWL: hind-paw withdrawal latency, HWT: hind-paw withdrawal threshold.
Data from nociceptive tests were presented as mean " S.E.M. with n s 9 per group. The difference between groups was determined by two-way analysis of variance ŽANOVA., U P - 0.05, UU P - 0.01 and UUU P - 0.001 were considered as significant. The notation of Fleftrleft , Fleftrright or Frightrright expresses the F-value in ANOVA, and left or right means left HWL Žor HWT. or right HWL Žor HWT.. Solutions for intrathecal administration were prepared with sterilized saline, each with a volume of 10 ml: Ž1. 26.6 nmol of morphine ŽMorphine Hydrochloride, Shenyang First Pharmaceutical Factory, China.; Ž2. 0.3, 1, or 3 nmol of galantide Žgalantide: galanin-Ž1–12.-pro-substance P-Ž5–11., Bachem, Feinchemikalien, Switzerland.. Control groups were given 10 ml of 0.9% saline. Thirty-six rats with mononeuropathy were divided into four groups receiving intrathecal injections of 26.6 nmol of morphine, followed 10 min later by: 0.3, 1 or 3 nmol of galantide or 10 ml of 0.9% saline as a control. The results are shown in Fig. 1. After the injection of morphine, the HWL and HWT increased in all four groups. Twenty minutes after intrathecal injection of galantide, the increased HWL and HWT were attenuated significantly in the groups of receiving 3 nmol Žhot-plate test: Fleftrleft s 9.49, P - 0.01; Frightrright s 14.32, P - 0.001. Randall Selitto test: Fleftrleft s 6.87, P - 0.05; Frightrright s 15.79, P - 0.001. and 1 nmol of galantide Žhot-plate test: Frightrright s 9.20, P - 0.01. Randall Selitto test: Fleftrleft s 4.52, P - 0.05; Frightrright s 18.20, P - 0.001. compared with the control group, with the exception of the hot-plate test in the left hind-paw Ž Fleftrleft s 2.05, P s 0.16.. In the group receiving 0.3 nmol of galantide, there were no significant changes compared with the control group.
The present results showed that the increased HWL and HWT induced by morphine were attenuated by intrathecal injection of 1 or 3 nmol of galantide, suggesting there is an interaction between galanin and opioids in mononeuropathy. The results are supported by the report in which galanin acted synergically with opioids to suppress the nociceptive flexor reflex in the spinal flexor reflex model w6x. Also, Reimann et al. w4x reported that the spinal antinociception elicited by morphine was antagonized by two types of galanin receptor antagonists, galantide and M35 Žgalanin-Ž1–13.-bradykikin-Ž2–9.-amid. in rats with inflammation. Similar findings were obtained by Selve et al. w5x who reported that galantide co-administered intrathecally with other antinociceptive drugs Žfor example, tramadol, wD-Ala-NMePhe-Gly-olx-enkephalin, DAMGO. reduced their antinociceptive effects. Recent study of our laboratory showed that the increased nociceptive response latencies induced by intra-periaqueductal grey injection of galanin was reversed by naloxone w7x. Taken together, it is possible that galanin as neuropeptide involved in the antinociception acts synergically with opioids to inhibit the nociceptive information transmission.
Acknowledgements This study was supported by the funds from Karolinska Institutet Foundation, Foundation for Acupuncture and Alternative Treatment Methods and National Natural Science Foundation of China ŽNSFC. and the Natural Science Research Foundation of Peking University.
Y.-P. Zhang et al.r Brain Research 852 (2000) 485–487
References w1x N. Attal, F. Jazat, V. Kayser, G. Guibaud, Further evidence for a ‘pain related’ behaviour in a model of unilateral peripheral mononeuropathy, Pain 41 Ž1990. 235–251. w2x G.J. Bennett, Y.K. Xie, A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man, Pain 33 Ž1988. 87–107. w3x B. Przewlocka, H. Machelska, P. Rekowski, G. Kupryszewski, R. Przewlocki, Intracerebroventricular galanin and N-terminal galanin fragment enhance the morphine-induced analgesia in the rat, J. Neural Transm. 102 Ž1995. 229–235. w4x W. Reimann, W. Englberger, E. Friderichs, N. Selve, B. Wilffert, Spinal antinociception by morphine in rats is antagonized by galanin receptor antagonists, Naunyn-Schmiedeberg’s Arch. Pharmacol. 350 Ž1994. 380–386.
487
w5x N. Selve, W. Englberger, E. Friderichs, H. Hennies, W. Reimann, B. Wilffert, Galanin receptor antagonists attenuate spinal antinociceptive effects of DAMGO, tramadol and non-opioid drugs in rats, Brain Res. 735 Ž1996. 177–187. w6x Z. Wiesenfeld-Hallin, X.J. Xu, M.J. Villar, T. Hokfelt, Intrathecal galanin potentiates the spinal analgesic effect of morphine: electrophysiological and behavioral studies, Neurosci. Lett. 109 Ž1990. 217–221. w7x D. Wang, H.H. Ye, L.C. Yu, T. Lundeberg, Intra-periaqueductal grey injection of galanin increases the nociceptive response latency in rats, an effect reversed by naloxone, Brain Res. 834 Ž1999. 152–154. w8x T.L. Yaksh, A.B. Malmberg, Central pharmacology of nociceptive transmission, in: P.D. Wall, R. Melzack ŽEds.., Textbook of Pain, 3rd edn. Churchill Livingstone, Edinburgh, 1994, pp. 165–200. w9x L.C. Yu, T. Lundeberg, H. An, F.X. Wang, T. Lundeberg, Effects of intrathecal galanin on nociceptive responses in rats with mononeuropathy, Life Sci. 64 Ž1999. 1145–1153.