Antinociceptive effects of dexmedetomidine via spinal substance P and CGRP

Ruiqin Li, Feng Qi, Junlong Zhang, Yong Ji, Dengxin Zhang, Zhiyun Shen, Weifu Lei, Ruiqin Li, Feng Qi, Junlong Zhang, Yong Ji, Dengxin Zhang, Zhiyun Shen, Weifu Lei

Abstract

The aim of this study was to examine the role played by substance P and calcitonin gene-related peptide (CGRP) within the dorsal horn of the spinal cord in engagement of antinociception evoked by dexmedetomidine (DEX). Paw withdrawal threshold (PWT) to mechanical stimulation was determined after chronic intrathecal infusion of DEX and enzyme-linked immunosorbent assay (ELISA) was employed to examine the levels of spinal substance P and CGRP. Our results show that PWT was significantly increased by intrathecal administration of DEX in rats (P < 0.05 vs. vehicle control, n = 20 in each group). Also, intrathecal infusion of DEX significantly decreased the concentrations of substance P and CGRP as compared with vehicle control (P < 0.05 DEX vs. vehicle control, n = 20 in each group). Blocking α2-adrenoreceptors (α2-AR) blunted the decreases of substance P and CGRP levels and the enhancement of PWT evoked by DEX. Additionally, a linear relationship was observed between PWT and the levels of spinal substance P (r = 0.87; P < 0.005) and CGRP (r = 0.85; P < 0.005). Moreover, blocking individual substance P and CGRP receptors amplified PWT without altering substance P and CGRP levels. Thus, DEX plays a role in stimulating α2-AR receptors, which thereby decreases substance P and CGRP levels within the dorsal horn. This contributes to DEX-evoked antinociception.

Keywords: Calcitonin gene-related peptide (CGRP); Dexmedetomidine; Dorsal horn; Pain modulation; Substance P.

Figures

Figure 1
Figure 1
Effects of dexmedetomidine (DEX). (A) The effects of DEX on paw withdrawal threshold (PWT). Intrathecal administration of DEX (50 μM) increased PWT in rats as compared with aCSF infusion. Blocking α2-AR blunted DEX-evoked effects. (B and C) Intrathecal adminstration of DEX decreased the concentrations of substance P and CGRP within the dorsal horn of the spinal cord. BRL44408 (50 μM), an antagonist of α2-AR, largely restored the levels of substance P and CGRP that were attenuated by DEX. Data are expressed as mean ± standard deviation. *P < 0.05 DEX vs. aCSF and DEX plus BRL44408. The number of rats = 20 in each of the aCSF and DEX groups; the number of rats in the group with DEX plus BRL44408 = 15. Legend: aCSF, artificial cerebrospinal fluid; CGRP, calcitonin gene-related peptide.
Figure 2
Figure 2
Linear relation analysis. There is a close relationship between paw withdrawal threshold (PWT) and the levels of spinal substance P (A), and between PWT and the levels of spinal CGRP (B). The number of animals is 20 for the aCSF control; 20 for dexmedetomidine (DEX) injection and 15 for DEX injection with prior administration of α2-AR inhibitor. Legend: CGRP, calcitonin gene-related peptide; aCSF, artificial cerebrospinal fluid.
Figure 3
Figure 3
Effects of blocking NK-1 and CGRP receptors on paw withdrawal threshold (PWT) and the levels of substance P and CGRP within the dorsal horn of the spinal cord. Intrathecal administration of antagonists to NK-1 (CP-96345, n = 10 at 300 nM) and CGRP receptors (n = 10, CGRP 8-37 at 2 mg/ml) significantly increased PWT as compared with only aCSF injection (n = 10) (A and B). However, the levels of substance P and CGRP within the dorsal horn were not significantly altered by blocking NK-1 and CGRP receptors (B and C). Data are expressed as mean ± standard deviation. *P < 0.05 vs. aCSF control. Legend: CGRP, calcitonin gene-related peptide; aCSF, artificial cerebrospinal fluid.

References

    1. Gerlach AT, Murphy CV, Dasta JF. An updated focused review of dexmedetomidine in adults. Ann Pharmacother. 2009;43:2064–2074.
    1. Paris A, Tonner PH. Dexmedetomidine in anaesthesia. Curr Opin Anaesthesiol. 2005;18:412–418.
    1. O’Connor M, Bucknall T, Manias E. Sedation management in Australian and New Zealand intensive care units: doctors’ and nurses’ practices and opinions. Am J Crit Care. 2010;19:285–295.
    1. Pandharipande PP, Pun BT, Herr DL, Maze M, Girard TD, Miller RR, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA. 2007;298:2644–2653.
    1. Riker RR, Shehabi Y, Bokesch PM, Ceraso D, Wisemandle W, Koura F, et al. Dexmedetomidine vs midazolam for sedation of critically ill patients: a randomized trial. JAMA. 2009;301:489–499.
    1. Cormack JR, Orme RM, Costello TG. The role of α2-agonists in neurosurgery. J Clin Neurosci. 2005;12:375–378.
    1. Zhang X, Bai X. New therapeutic uses for an α2 adrenergic receptor agonist - dexmedetomidine in pain management. Neurosci Lett. 2014;561:7–12.
    1. Happe HK, Coulter CL, Gerety ME, Sanders JD, O’Rourke M, Bylund DB, et al. α-2 adrenergic receptor development in rat CNS: an autoradiographic study. Neuroscience. 2004;123:167–178.
    1. Huang Y, Stamer WD, Anthony TL, Kumar DV, St John PA, Regan JW. Expression of α2-adrenergic receptor subtypes in prenatal rat spinal cord. Dev Brain Res. 2002;133:93–104.
    1. Shi TS, Winzer-Serhan U, Leslie F, Hökfelt T. Distribution and regulation of α2-adrenoceptors in rat dorsal root ganglia. Pain. 2000;84:319–330.
    1. Hunter JC, Fontana DJ, Hedley LR, Jasper JR, Lewis R, Link RE, et al. Assessment of the role of α2-adrenoceptor subtypes in the antinociceptive, sedative and hypothermic action of dexmedetomidine in transgenic mice. Br J Pharmacol. 1997;122:1339–1344.
    1. Mansikka H, Lahdesmaki J, Scheinin M, Pertovaara A. α2A adrenoceptors contribute to feedback inhibition of capsaicin-induced hyperalgesia. Anesthesiology. 2004;101:185–190.
    1. Hua X-Y, Yaksh TL. Dorsal horn substance P and NK1 receptors: study of a model system in spinal nociceptive processing. In: Malcangio M, editor. Synaptic plasticity in pain. Springer; London: 2009. pp. 109–138.
    1. Fehrenbacher JC, Taylor CP, Vasko MR. Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain. 2003;105:133–141.
    1. de Souza GG, Duarte ID, de Castro Perez A. Differential involvement of central and peripheral α2 adrenoreceptors in the antinociception induced by aerobic and resistance exercise. Anesth Analg. 2013;116:703–711.
    1. Takano M, Takano Y, Yaksh TL. Release of calcitonin gene-related peptide (CGRP), substance P (SP), and vasoactive intestinal polypeptide (VIP) from rat spinal cord: modulation by α2 agonists. Peptides. 1993;14:371–378.
    1. Liu L, Shenoy M, Pasricha PJ. Substance P and calcitonin gene related peptide mediate pain in chronic pancreatitis and their expression is driven by nerve growth factor. JOP. 2011;12:389–394.
    1. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods. 1994;53:55–63.
    1. Wang D, Zhao J, Wang J, Li J, Yu S, Guo X. Deficiency of female sex hormones augments PGE and CGRP levels within midbrain periaqueductal gray. J Neurol Sci. 2014;346:107–111.
    1. MacDonald E, Kobilka BK, Scheinin M. Gene targeting - homing in on α2-adrenoceptor-subtype function. Trends Pharmacol Sci. 1997;18:211–219.
    1. Ishii H, Kohno T, Yamakura T, Ikoma M, Baba H. Action of dexmedetomidine on the substantia gelatinosa neurons of the rat spinal cord. Eur J Neurosci. 2008;27:3182–3190.
    1. Zheng Y, Cui S, Liu Y, Zhang J, Zhang W, Zhang J, et al. Dexmedetomidine prevents remifentanil-induced postoperative hyperalgesia and decreases spinal tyrosine phosphorylation of N-methyl-D-aspartate receptor 2B subunit. Brain Res Bull. 2012;87:427–431.
    1. Chiu KM, Lin TY, Lu CW, Wang SJ. Inhibitory effect of glutamate release from rat cerebrocortical nerve terminals by α2 adrenoceptor agonist dexmedetomidine. Eur J Pharmacol. 2011;670:137–147.
    1. Kimura M, Saito S, Obata H. Dexmedetomidine decreases hyperalgesia in neuropathic pain by increasing acetylcholine in the spinal cord. Neurosci Lett. 2012;529:70–74.
    1. Kamisaki Y, Hamada T, Maeda K, Ishimura M, Itoh T. Presynaptic α2 adrenoceptors inhibit glutamate release from rat spinal cord synaptosomes. J Neurochem. 1993;60:522–526.
    1. Pan YZ, Li DP, Pan HL. Inhibition of glutamatergic synaptic input to spinal lamina IIo neurons by presynaptic α2-adrenergic receptors. J Neurophysiol. 2002;87:1938–1947.
    1. Shirasaka T, Kannan H, Takasaki M. Activation of a G protein-coupled inwardly rectifying K+ current and suppression of Ih contribute to dexmedetomidine-induced inhibition of rat hypothalamic paraventricular nucleus neurons. Anesthesiology. 2007;107:605–615.
    1. Hayashida K, Eisenach JC. Spinal α2-adrenoceptor-mediated analgesia in neuropathic pain reflects brain-derived nerve growth factor and changes in spinal cholinergic neuronal function. Anesthesiology. 2010;113:406–412.
    1. Hayashida K, Peters CM, Gutierrez S, Eisenach JC. Depletion of endogenous noradrenaline does not prevent spinal cord plasticity following peripheral nerve injury. J Pain. 2012;13:49–57.
    1. Hayashida K, Eisenach JC. A tropomyosine receptor kinase inhibitor blocks spinal neuroplasticity essential for the anti-hypersensitivity effects of gabapentin and clonidine in rats with peripheral nerve injury. J Pain. 2011;12:94–100.
    1. Chen Y, Zhao Z, Code WE, Hertz L. A correlation between dexmedetomidine-induced biphasic increases in free cytosolic calcium concentration and energy metabolism in astrocytes. Anesth Analg. 2000;91:353–357.
    1. Liu L, Ji F, Liang J, He H, Fu Y, Cao M. Inhibition by dexmedetomidine of the activation of spinal dorsal horn glias and the intracellular ERK signaling pathway induced by nerve injury. Brain Res. 2012;1427:1–9.
    1. Guneli E, Karabay Yavasoglu NU, Apaydin S, Uyar M, Uyar M. Analysis of the antinociceptive effect of systemic administration of tramadol and dexmedetomidine combination on rat models of acute and neuropathic pain. Pharmacol Biochem Behav. 2007;88:9–17.
    1. Ulger F, Bozkurt A, Bilge SS, Ilkaya F, Dilek A, Bostanci MO, et al. The antinociceptive effects of intravenous dexmedetomidine in colorectal distension-induced visceral pain in rats: the role of opioid receptors. Anesth Analg. 2009;109:616–622.
    1. Overland AC, Kitto KF, Chabot-Dore AJ, Rothwell PE, Fairbanks CA, Stone LS, et al. Protein kinase C mediates the synergistic interaction between agonists acting at α2-adrenergic and δ-opioid receptors in spinal cord. J Neurosci. 2009;29:13264–13273.
    1. Tamagaki S, Suzuki T, Hagihira S, Hayashi Y, Mashimo T. Systemic daily morphine enhances the analgesic effect of intrathecal dexmedetomidine via up-regulation of α2 adrenergic receptor subtypes A, B and C in dorsal root ganglion and dorsal horn. J Pharm Pharmacol. 2010;62:1760–1767.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa