Beta-1 adrenoceptor blockade decreases the firing rate to painful stimuli in spinal wide-dynamic range neurons in rats
Main Article Content
Keywords
Adrenergic receptors, Acute pain, Metroprolol, Adrenergic beta-antagonists
Abstract
Background: It is known that epinephrine/norepinephrine inhibit acute pain transmission. However, the role of β-adrenoceptors is not clear. Thus, we analyzed if β-1 and/or β-2 adrenoceptors can modulate acute pain transmission by performing in vivo single unit recordings during painful and non-painful peripheral stimulation in rats.
Methods: Longitudinal study in which we analyzed seven groups of male rats Wistar: control group (n = 11): saline (0.9 %); EPI group (n = 8): epinephrine 100 mcg; AGOβ1 group (n = 8): dobutamine 125 mcg; ANTβ1 group (n = 9): metoprolol 100 mcg; AGOβ2 group (n = 7): clenbuterol 100 mcg; ANTβ2 group (n = 8): butoxamine 100 mcg; ANTβ1 + EPI group (n = 10): metoprolol 100 mcg + epinephrine 100 mcg. For the statistical analysis we used ANOVA.
Results: Epinephrine significantly reduced the basal firing rate (BFR) in 34.1 % (p < 0.05) and also the evoked response by painful stimulation in 56 % (p < 0.05). No change was observed in the evoked response by non-painful stimulation. ANTβ1 was the only β-adrenoceptor acting drug that significantly reduced the evoked response by painful stimulation in 41 % (p < 0.05). None of the other drugs alone affected either the BFR or the evoked response to non-painful or painful stimulation.
Conclusion: It is the first time that a β1-adrenoceptor antagonist (metoprolol) probes to be effective in reducing the response to painful stimulation in WDR neurons.
References
Butler RK, Finn DP. Stress-induced analgesia. Prog Neurobiol. 2009;88(3):184-202.
Akil H, Young E, Walker JM, Watson SJ. The many possible roles of opioids and related peptides in stress-induced analgesia. Ann NY Acad Sci. 1986;467:140-53.
Hohmann AG, Suplita RL, Bolton NM, Neely MH, Fegley D, Mangieri R, et al. An endocannabinoid mechanism for stress-induced analgesia. Nature. 2005 Jun 23;435(7045):1108-12.
Killian P, Holmes BB, Takemori AE, Portoghese PS, Fujimoto JM. Cold water swim stress- and delta-2 opioid-induced analgesia are modulated by spinal gamma-aminobutyric acidA receptors. J Pharmacol Exp Ther. 1995 Aug;274(2):730-4.
Lico MC, Hoffmann A, Covian MR. Influence of some limbic structures upon somatic and autonomic manifestations of pain. Physiol Behav. 1974 May;12(5):805-11.
Helmstetter FJ, Tershner SA. Lesions of the periaqueductal gray and rostral ventromedial medulla disrupt antinociceptive but not cardiovascular aversive conditional responses. J Neurosci. 1994. 14(11):7099-108.
Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965(150);971-9.
Moayedi M, Davis KD. Theories of pain: from specificity to gate control. J Neurophysiol. 2013 Jan;109(1):5-12. doi: 10.1152/jn.00457.2012. Epub 2012 Oct 3.
Collins JG, Kitahata LM, Matsumoto M, Homma E, Suzukawa M. Spinally administered epinephrine suppresses noxiously evoked activity of WDR neurons in the dorsal horn of the spinal cord. Anesthesiology. 1984 Apr;60(4):269-275.
Maeda M, Tsuruoka M, Hayashi B, Nagasawa I, Inoue T. Descending pathways from activated locus coeruleus/subcoeruleus following unilateral hindpaw inflammation in the rat. Brain Res Bull. 2009 Mar 16;78(4-5):170-4. doi: 10.1016/j.brainresbull.2008.09.005.
Danzebrink RM, Gebhart GF. Antinociceptive effects of intrathecal adrenoceptor agonists in a rat model of visceral nociception. J Pharmacol Exp Ther. 1990 May;253(2):698-705.
Fukuda T, Furukawa H, Hisano S, Toyooka H. Systemic clonidine activates neurons of the dorsal horn, but not the locus coeruleus (A6) or the A7 area, after a formalin test: the importance of the dorsal horn in the antinociceptive effects of clonidine. J Anesth. 2006;20(4):279-83.
Takano Y, Yaksh TL. Characterization of the pharmacology of intrathecally administered alpha-2 agonists and antagonists in rats. J Pharmacol Exp Ther. 1992 May;261(2):764-72.
Sierralta F, Naquira D, Pinardi G, Miranda HF. alpha-Adrenoceptor and opiod receptor modulation of clonidine-induced antinociception. Br J Pharmacol. Oct 1996; 119(3):551-4
Siegel GJ, Agranoff BW, Albers RW, Fisher SK, Uhler MD. Basic Neurochemistry: Molecular, Cellular and Medical Aspects. Sixth ed. Lippincott-Raven: Philadelphia; 1999.
Atlas D, Melamed E. Direct mapping of beta-adrenergic receptors in the rat central nervous system by a novel fluorescent beta-blocker. Brain Res. 1978 Jul 14;150(2):377-85.
Choucair-Jaafar N, Yalcin I, Rodeau JL, Waltisperger E, Freund-Mercier MJ, Barrot M. Beta2-adrenoceptor agonists alleviate neuropathic allodynia in mice after chronic treatment. Br J Pharmacol. 2009 Dec;158(7):1683-94. doi: 10.1111/j.1476-5381.2009.00510.x.
Khanna NK, Dadhich AP, Vyas DS. Modification of morphine analgesia by labetalol. Indian J Exp Biol. 1978 Oct;16(10):1091-2.
Masaki E. Antinociceptive effects of landiolol and esmolol. Masui. 2006 Jul;55(7):849-55. Review. Japanese.
Light KC, Bragdon EE, Grewen KM, Brownley KA, Girdler SS, Maixner W. Adrenergic dysregulation and pain with and without acute beta-blockade in women with fibromyalgia and temporomandibular disorder. J Pain. 2009 May;10(5):542-52. doi: 10.1016/j.jpain.2008.12.006.
Ashtari F, Shaygannejad V, Akbari M. A double-blind, randomized trial of low-dose topiramate vs propranolol in migraine prophylaxis. Acta Neurol Scand. 2008 Nov;118(5):301-5. doi: 10.1111/j.1600-0404.2008.01087.x.
Marsland AR, Weekes JW, Atkinson RL, Leong MG. Phantom limb pain: a case for beta blockers? Pain. 1982 Mar;12(3):295-7.
Barrot M, Yalcin I, Choucair-Jaafar N, Benbouzid M, Freund-Mercier MJ. From antidepressant drugs to beta-mimetics: preclinical insights on potential new treatments for neuropathic pain. Recent Pat CNS Drug Discov. 2009 Nov;4(3):182-9.
Zimmermann M. Ethical guidelines for investigations of experimental pain in conscious animals. (Guest Editorial). Pain. 1983 Jun;16(2):109-10.
Svendsen F, Hole K, Tjølsen A. Long-term potentiation in single wide dynamic range neurons induced by noxious stimulation in intact and spinalized rats. Prog Brain Res. 2000;129:153-61.
Bouhassira D, Bing Z, Le Bars D. Studies of brain structures involved in diffuse noxious inhibitory controls in the rat: the rostral ventromedial medulla. J Physiol. 1993 Apr;463:667-87.
Dickenson A, Ashwood N, Sullivan AF, James I, Dray A. Antinociception produced by capsaicin: spinal or peripheral mechanism? Eur J Pharmacol. 1990 Oct 9;187(2):225-33.
Eisenach JC, DuPen S, Dubois M, Miguel R, Allin D. The epidural clonidine study group. Epidural clonidine analgesia for intractable cancer pain. Pain. 1995 Jun;61(3):391-9.
Nicholas AP, Hokfelt T, Pieribone VA. The distribution and significance of CNS adrenoceptors examined with in situ hybridization. Trends Pharmacol Sci 17:245-55.
Pertovaara A, Almeida A. Endogenous pain modulation: descending inhibitory systems, in Handbook of Clinical Neurology, Pain. 3rd series, vol. 3, 2006, pp. 179-192.
Kobilka BK. Structural insights into adrenergic receptor function and pharmacology. Trends Pharmacol Sci. Apr 2011; 32(4): 213-8.
Melzack R, Wall PD. On the nature of cutaneous sensory mechanisms. Brain. 1962;85(2):331-56 doi:10.1093/brain/85.2.331