백서의 척수신경결찰모델에서 Morphine의 투여가 항이질통 효과와 척수 α2 아드레날린계 수용체 아형 mRNA 발현에 미치는 영향
The Antiallodynic Effect and the Change of the α2 Adrenergic Receptor Subtype mRNA Expression by Morphine Administration in a Spinal Nerve Ligation Rat Model
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Background: The neuropathic pain arising from nerve injury is difficult to treat and the therapeutic effects of opioid drugs remain debatable. Agonists acting at the α2 adrenergic and opioid receptors have analgesic properties and they act synergistically when co-administered in the spinal cord. The lack of subtype-selective pharmacological agents has previously impeded the synergistic effects that are mediated by the adrenergic receptor subtypes. Methods: We created neuropathic pain model by ligating the L5 spinal nerve in Sprague-Dawley rats (n = 18). We divided the rats into three groups (n = 6 for each group), and we administered intraperitoneal morphine (1 ㎎/㎏, 3 ㎎/㎏, 5 ㎎/㎏) and then we measured the mechanical allodynia with using von-Frey filaments for 8 hours. We then injected morphine (5 ㎎/㎏) intraperitoneally, twice a day for 2 weeks. We measured the tactile and cold allodynia in the morphine group (n = 9) and the saline group (n = 9). After 2 weeks, we decapitated the rats and harvested the spinal cords at the level of lumbar enlargement. We compared the α2 subtype mRNA expression with that of control group (n = 6) by performing real time polymerase chain reaction (RTPCR). Results: Intraperitoneal morphine reduced the neuropathic pain behavior in the dose-dependent manner. Chronic morphine administration showed an antiallodynic effect on the neuropathic pain rat model. The rats did not display tolerance or hyperalgesia. The expression of the mRNAs of the α2A, α2B, α2C subtypes decreased, and morphine attenuated this effect. But we could not get statistically proven results. Conclusions: Systemic administration of morphine can attenuate allodynia during both the short-term and long-term time course. Morphine has an influence on the expression of α2 receptor subtype mRNA. Yet we need more research to determine the precise effect of morphine on the α2 subtype gene expression.
Abstract
Background: The neuropathic pain arising from nerve injury is difficult to treat and the therapeutic effects of opioid drugs remain debatable. Agonists acting at the α2 adrenergic and opioid receptors have analgesic properties and they act synergistically when co-administered in the spinal cord. The lack of subtype-selective pharmacological agents has previously impeded the synergistic effects that are mediated by the adrenergic receptor subtypes. Methods: We created neuropathic pain model by ligating the L5 spinal nerve in Sprague-Dawley rats (n = 18). We divided the rats into three groups (n = 6 for each group), and we administered intraperitoneal morphine (1 ㎎/㎏, 3 ㎎/㎏, 5 ㎎/㎏) and then we measured the mechanical allodynia with using von-Frey filaments for 8 hours. We then injected morphine (5 ㎎/㎏) intraperitoneally, twice a day for 2 weeks. We measured the tactile and cold allodynia in the morphine group (n = 9) and the saline group (n = 9). After 2 weeks, we decapitated the rats and harvested the spinal cords at the level of lumbar enlargement. We compared the α2 subtype mRNA expression with that of control group (n = 6) by performing real time polymerase chain reaction (RTPCR). Results: Intraperitoneal morphine reduced the neuropathic pain behavior in the dose-dependent manner. Chronic morphine administration showed an antiallodynic effect on the neuropathic pain rat model. The rats did not display tolerance or hyperalgesia. The expression of the mRNAs of the α2A, α2B, α2C subtypes decreased, and morphine attenuated this effect. But we could not get statistically proven results. Conclusions: Systemic administration of morphine can attenuate allodynia during both the short-term and long-term time course. Morphine has an influence on the expression of α2 receptor subtype mRNA. Yet we need more research to determine the precise effect of morphine on the α2 subtype gene expression.
참고문헌 (26)
- Suzuki R, "The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain", Pain, 80, pp.215~228 (1999)
- Kim SK, "Effects of alpha1- and alpha2-adrenoreceptor antagonists on cold allodynia in a rat tail model of neuropathic pain", Brain Res, 1039, pp.207~210 (2005)
- Aantaa R, "Molecular pharmacology of alpha 2-adrenoceptor subtypes", Ann Med, 27, pp.439~449 (1995)
- Stone LS, "The alpha2a adrenergic receptor subtype mediates spinal analgesia evoked by alpha2 agonists and is necessary for spinal adrenergic-opioid synergy", J Neurosci, 17, pp.7157~7165 (1997)
- -mediated spinal antinociception and synergy with opioids persists in the absence of functional alpha-2A- or alpha-2C-adrenergic receptors, "J Pharmacol Exp Ther", 2007, 899~906
- Kim SH, "An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat", Pain, 50, pp.355~363 (1992)
- 한동우, "Antiallodynic Effect of Pregabalin in Rat Models of Sympathetically Maintained and Sympathetic Independent Neuropathic Pain", Yonsei Medical Journal, 48(1), pp.41~47 (2007), 연세대학교의과대학
- 김태완, "백서의 척수신경결찰 모델에서 α2 아드레날린 수용체 변화와 Tramadol의 효과", Korean Journal of Anesthesiology, 52(3), pp.328~334 (2007), 대한마취과학회
- Duflo F, "Peripheral nerve injury alters the alpha2 adrenoceptor subtype activated by clonidine for analgesia", Anesthesiology, 97, pp.636~641 (2002)
- Zhao C, "Antiallodynic effects of systemic and intrathecal morphine in the spared nerve injury model of neuropathic pain in rats", Anesthesiology, 100, pp.905~911 (2004)
- Besse D, "Regulation of opioid binding sites in the superficial dorsal horn of the rat spinal cord following loose ligation of the sciatic nerve: Comparison with sciatic nerve section and lumbar dorsal rhizotomy", Neuroscience, 50, pp.921~933 (1992)
- Goff JR, "Reorganization of the spinal dorsal horn in models of chronic pain: correlation with behaviour", Neuroscience, 82, pp.559~574 (1998)
- Yu W, "Comparison of the anti-allodynic and antinociceptive effects of systemic; intrathecal and intracerebroventricular morphine in a rat model of central neuropathic pain", Eur J Pain, 1, pp.17~29 (1997)
- Bian D, "Characterization of the antiallodynic efficacy of morphine in a model of neuropathic pain in rats", Neuroreport, 6, pp.1981~1984 (1995)
- Przewlocka B, "Spinal analgesic action of endomorphins in acute, inflammatory and neuropathic pain in rats", Eur J Pharmacol, 367, pp.189~196 (1999)
- Zollner C, "Chronic morphine use does not induce peripheral tolerance in a rat model of inflammatory pain", J Clin Invest, 118, pp.1065~1073 (2008)
- Woolf CJ, "Transcriptional and posttranslational plasticity and the generation of inflammatory pain", Proc Natl Acad Sci USA, 96, pp.7723~7730 (1999)
- 정규연, "신경병증성 통증모델에서 신경영양인자 유도물질의 반복 투여가 척수 아드레날린계에 미치는 영향", The Korean Journal of Pain, 21(3), pp.179~186 (2008), 대한통증학회
- Stone LS, "Effects of peripheral nerve injury on alpha-2A and alpha-2C adrenergic receptor immunoreactivity in the rat spinal cord", Neuroscience, 93, pp.1399~1407 (1999)
- Wei H, "Spinal and pontine alpha2-adrenoceptors have opposite effects on pain-related behavior in the neuropathic rat", Eur J Pharmacol, 551, pp.41~49 (2006)
- Nicholas AP, "Distributions of mRNAs for alpha-2 adrenergic receptor subtypes in rat brain: An in situ hybridization study", J Comp Neurol, 328, pp.575~594 (1993)
- Leiphart JW, "Decreased spinal alpha2a- and alpha2c-adrenergic receptor subtype mRNA in a rat model of neuropathic pain", Neurosci Lett, 349, pp.5~8 (2003)
- Shi TS, "Distribution and regulation of alpha(2)-adrenoceptors in rat dorsal root ganglia", Pain, 84, pp.319~330 (2000)
- Shi TJ, "Distribution of alpha2-adrenoceptor mRNAs in the rat lumbar spinal cord in normal and axotomized rats", Neuroreport, 10, pp.2835~2839 (1999)
- Ongioco RR, "Alpha2-adrenergic receptors in human dorsal root ganglia: Predominance of alpha2b and alpha2c subtype mRNAs", Anesthesiology, 92, pp.968~976 (2000)
- Chen YP, "Effect of morphine on deep dorsal horn projection neurons depends on spinal GABAergic and glycinergic tone: implications for reduced opioid effect in neuropathic pain", J Pharmacol Exp Ther, 315, pp.696~703 (2005)