The precise effects of systemic administration of midazolam on nociception are unclear. Antinociceptive effects (3–5,7,8), hyperalgesic effects (9,10), and lack of effects on nociception (11–13) have been reported. In the present study, we found that IV administration of midazolam produced dose-related effects on SSR discharges in anesthetized cats.
Administration of 0.1 mg/kg and 0.5 mg/kg significantly depressed C reflex discharges in brain-intact cats. In particular, the dose of 0.1 mg/kg significantly depressed C reflex discharges but not Aδ reflex discharges. These observations suggest that midazolam has antinociceptive effects at these doses. In the group treated with 0.5 mg/kg, C reflex discharges recovered rapidly and acutely after IV administration of flumazenil. Flumazenil competitively inhibits the binding of benzodiazepine to the GABAA receptor complexes and does not act on peripheral benzodiazepine receptors, which are not associated with the GABA system (25–27). In a preliminary study, flumazenil alone at the dosage we used was found not to affect SSR discharges (unpublished data). It thus appears that GABAA receptor complexes are involved in mediating the depressive effects of midazolam on C reflex discharges.
Depression of SSR discharges by midazolam was still apparent in decerebrate cats, suggesting that the infra-midbrain region, including the RVLM and the spinal cord, is a major site of action for the antinociceptive effects of midazolam. The magnitudes of depression of C reflex discharge were significantly greater in decerebrate cats than in brain-intact cats. It has been suggested that there might be tonic descending inhibitory modulation from the supra-midbrain region on the pathway of the SSR (20). A high density of specific benzodiazepine binding sites has been noted in the supra-midbrain region (28). It is possible that midazolam acts on the supra-midbrain region, inhibits descending inhibitory modulation, and thus attenuates the depressive effects on SSR discharges. Control amplitudes of SSR appeared to be greater in decerebrate cats than in intact cats (Table 1). This finding is consistent with the suggestion of Ogawa et al. (20) that there might be tonic descending inhibitory modulation from the supra-midbrain region on the pathway of the SSR.
The present study did not determine the precise site of midazolam-mediated depression of SSR discharges. Numerous investigations have suggested that the antinociceptive effects of benzodiazepines are modulated in the dorsal horn of the spinal cord (3–5,7). However, endogenous GABA is involved in mediating the tonic inhibition of vasopressor neurons in the RVLM (29). It has been suggested that vasopressor responses of RVLM to nociception are inhibited by GABAA receptor binding (30,31). Specific benzodiazepine binding sites have also been identified in the intermediolateral nuclei of the spinal cord, which include sympathetic preganglionic neurons (32). These sites could not be excluded as possible sites of midazolam-mediated depression of SSR discharges.
In contrast, C reflex discharges were augmented by administration of 0.03 mg/kg in brain-intact cats. This finding suggests that, at this dose, midazolam reduces the nociceptive threshold. Augmentation of C reflex discharges at this dose of midazolam is consistent with the findings on the viscero-somatic reflex obtained by Crawford et al. (5). They demonstrated that, in rabbits, a small dose of midazolam (62.5 μg/kg) injected IM could produce hyperalgesic effects whereas a large dose (250 μg/kg) could produce antinociceptive effects (5). Studies based on hotplate and/or tail-flick tests have suggested that midazolam induces antinociceptive effects at the spinal level and hyperalgesic effects at the supraspinal level (10,33,34). Hence, the effects of midazolam on nociception appear to depend on its site of action and its dosage. In addition, it should be noted that our findings parallel those for barbiturates, in which spinothalamic tract neurons exhibited increased responses to peripheral C-fiber volleys and decreased responses to A-fiber volleys after small doses of pentobarbital (35).
There are a few limitations to this study. First, it is difficult with SSR experiments to compare absolute SSR discharges among groups, because the absolute amplitude of SSR discharges obtained exhibits a very large range of individual difference. SSR discharges were therefore computed as percentages of the control under conditions in which they were clearly elicited by supramaximal stimulation and stable control values had been confirmed. Second, the cats were premedicated with IM ketamine, which has antinociceptive properties. However, we have already examined the effects of ketamine on SSR discharges (36), and have demonstrated that the significant depressive effects of IV ketamine (10 mg/kg) on SSR discharges occur within 10 min in brain-intact cats and within 20 min in decerebrate cats, with spontaneous recovery of all averaged values to the control level within 60 min (36). Moreover, stable control values of SSR discharges were repeatedly confirmed before administration of midazolam in the present study. We therefore believe that ketamine had little effect on our results. Third, the animals had been vagotomized bilaterally at the cervical level to prevent vagal input from influencing cardiac sympathetic nerve activity in this study. The cardiac vagal nerves make a small contribution to the cardiac SSR in cats (37). It has been reported that stimulation of the superficial peroneal nerve at strengths sufficient to excite both Aδ and C fibers gives rise to a brief period of bradycardia of small magnitude followed by more pronounced tachycardia in cats with intact vagal nerves, whereas cutting both vagal nerves results in the complete disappearance of bradycardia (37). This bradycardic response was thus because of the activation of vagal efferents to the heart. In clinical settings in which the vagal nerves are intact, SSR discharges might be somewhat suppressed.
In conclusion, our findings demonstrated dose-related effects of IV-administered midazolam on the SSR discharges in anesthetized cats. The clinical implication of these findings is that the effect of midazolam on nociception depends on its dosage. It also appears that the infra-midbrain region plays a major role in mediating the depressive effects of midazolam on the somatosympathetic C reflex discharges.
1. Niv D, Whitwam JG, Loh L. Depression of nociceptive sympathetic reflexes by the intrathecal administration of midazolam. Br J Anaesth 1983;55:541–7
2. Goodchild CS, Serrao JM. Intrathecal midazolam in the rat: evidence for spinally-mediated analgesia. Br J Anaesth 1987;59: 1563–70
3. Edwards M, Serrao JM, Gent JP, Goodchild CS. On the mechanism by which midazolam causes spinally mediated analgesia. Anesthesiology 1990;73:273–7
4. Wang C, Chakrabarti MK, Galletly DC, Whitwam JG. Relative effects of intrathecal administration of fentanyl and midazolam on A delta and C fiber reflexes. Neuropharmacology 1992;31:439–44
5. Crawford ME, Jensen FM, Toftdahl DB, Madsen JB. Direct spinal effect of intrathecal and extradural midazolam on visceral noxious stimulation in rabbits. Br J Anaesth 1993;70: 642–6
6. Bahar M, Cohen ML, Grinshpon Y, Chanimov M. Spinal anaesthesia with midazolam in the rat. Can J Anaesth 1977;44:208–15
7. Sumida T, Tagami M, Ide Y, Nagase M, Sekiyama H, Hanaoka K. Intravenous midazolam suppresses noxiously evoked activity of spinal wide dynamic range neurons in cats. Anesth Analg 1995;80:58–63
8. Kohno T, Kumamoto E, Baba H, Ataka T, Okamoto M, Shimoji K, Yoshimura M. Actions of midazolam on GABAergic transmission in substantia gelatinosa neurons of adult rat spinal cord slices. Anesthesiology 2000;92:507–15
9. Tatsuo MA, Salgado JV, Yokoro CM, Duarte ID, Francischi JN. Midazolam-induced hyperalgesia in rats: modulation via GABA(A) receptors at supraspinal level. Eur J Pharmacol 1999;370:9–15
10. Orii R, Ohashi Y, Halder S, Giombini M, Maze M, Fujinaga M. GABAergic interneurons at supraspinal and spinal levels differentially modulate the antinociceptive effect of nitrous oxide in Fischer rats. Anesthesiology 2003;98:1223–30
11. Daghero AM, Bradley EL, Kissin I. Midazolam antagonizes the analgesic effect of morphine in rats. Anesth Analg 1987;66:944–7
12. Rodgers JR, Randall JI. Benzodiazepine ligands, nociception and defeat analgesia in male mice. Psychopharmacology (Berl) 1987;91:305–15
13. Rosland JH, Hole K. 1,4-Benzodiazepines antagonize opiate-induced antinociception in mice. Anesth Analg 1990;71: 242–8
14. Sato A, Schmidt RF. Somatosympathetic reflexes: afferent fibers, central pathways, discharge characteristics. Physiol Rev 1973;53: 916–47
15. Morrison SF, Reis DJ. Reticulospinal vasomotor neurons in the RVL mediate the somatosympathetic reflex. Am J Physiol 1989;256: R1084–97
16. Reis DJ, Ruggiero DA, Morrison SF. The C1 area of the rostral ventrolateral medulla oblongata. Am J Hypertens 1989;2:S363–74
17. Ito K, Nakamura H, Sato A, Sato Y. Depressive effect of morphine on the sympathetic reflex elicited by stimulation of unmyelinated hindlimb afferent nerve fibers in anesthetized cats. Neurosci Lett 1983;39:169–73
18. Niv D, Whitwam JG. Selective effect of fentanyl on group III and IV somatosympathetic reflexes. Neuropharmacology 1983;22:703–9
19. Kato J, Meguro K, Sato A, Sato Y. The effects of morphine administered into the vertebral artery on the somatosympathetic A- and C-reflexes in anesthetized cats. Neurosci Lett 1992;138:207–10
20. Ogawa S, Saito H, Saeki S, Suzuki H. Reflex sympathetic activities during inhalation of anesthetics in cats: nitrous oxide. Neurosci Lett 1994;168:16–18
21. Lindenauer PK, Pekow P, Wang K, Mamidi DK, Gutierrez B, Benjamin EM. Perioperative beta-blocker therapy and mortality after major noncardiac surgery. N Engl J Med 2005;353:349–61
22. Mangano DT, Layug EL, Wallace A, Tateo I. Effect of atenolol on mortality and cardiovascular morbidity after noncardiac surgery. Multicenter Study of Perioperative Ischemia Research Group. N Engl J Med 1996;335:1713–20
23. Poldermans D, Boersma E, Bax JJ, Thomson IR, van de Ven LL, Blankensteijn JD, Baars HF, Yo TI, Trocino G, Vigna C, Roelandt JR, van Urk H. The effect of bisoprolol on perioperative mortality and myocardial infarction in high-risk patients undergoing vascular surgery. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. N Engl J Med 1999;341:1789–94
24. Fleisher LA, Beckman JA, Brown KA, Calkins H, Chaikof E, Fleischmann KE, Freeman WK, Froehlich JB, Kasper EK, Kersten JR, Riegel B, Robb JF, Smith SC Jr, Jacobs AK, Adams CD, Anderson JL, Antman EM, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Hunt SA, Lytle BW, Nishimura R, Page RL, Riegel B; American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Committee to Update the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery; American Society of Echocardiography; American Society of Nuclear Cardiology; Heart Rhythm Society; Society of Cardiovascular Anesthesiologists; Society for Cardiovascular Angiography and Interventions; Society for Vascular Med and Biology. ACC/AHA 2006 guideline update on perioperative cardiovascular evaluation for noncardiac surgery: focused update on perioperative beta-blocker therapy: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery): developed in collaboration with the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society for Vascular Medicine and Biology. Circulation 2006;113:2662–74
25. Marangos PJ, Patel J, Boulenger JP, Clark-Rosenberg R. Characterization of peripheral-type benzodiazepine binding sites in brain using [3H]Ro 5-4864. Mol Pharmacol 1982;22:26–32
26. Amrein R, Hetzel W, Bonetti EP, Gerecke M. Clinical pharmacology of midazolam and flumazenil. Resuscitation 1988;16:S5–27
27. Wilms H, Claasen J, Rohl C, Sievers J, Deuschl G, Lucius R. Involvement of benzodiazepine receptors in neuroinflammatory and neurodegenerative diseases: evidence from activated microglial cells in vitro. Neurobiol Dis 2003;14:417–24
28. Mohler H, Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science 1977;198:849–51
29. Amano M, Kubo T. Involvement of both GABAA and GABAB receptors in tonic inhibitory control of blood pressure at the rostral ventrolateral medulla of the rat. Naunyn Schmiedebergs Arch Pharmacol 1993;348:146–53
30. Sun MK, Spyer KM. Nociceptive inputs into rostral ventrolateral medulla-spinal vasomotor neurones in rats. J Physiol 1991;436:685–700
31. Kato G, Yasaka T, Katafuchi T, Furue H, Mizuno M, Iwamoto Y, Yoshimura M. Direct GABAergic and glycinergic inhibition of the substantia gelatinosa from the rostral ventromedial medulla revealed by in vivo patch-clamp analysis in rats. J Neurosci 2006;26:1787–94
32. Faul RLM, Villiger JW. Benzodiazepine receptors in the human spinal cord: a detailed anatomical and pharmacological study. Neuroscience 1986;17:791–802
33. Luger TJ, Hayashi T, Lorenz IH, Hill HF. Mechanisms of the influence of midazolam on morphine antinociception at spinal and supraspinal levels in rats. Eur J Pharmacol 1994;271:421–31
34. Niv D, Davidovich S, Geller E, Urca G. Analgesic and hyperalgesic effects of midazolam: dependence on route of administration. Anesth Analg 1988;67:1169–73
35. Hori Y, Lee KH, Chung JM, Endo K, Willis WD. The effects of small doses of barbiturate on the activity of primate nociceptive tract cells. Brain Res 1984;307:9–15
36. Iwasaki K, Kato J, Saeki S, Ogawa S. Effects of ketamine on somatosympathetic reflex discharges in cats. Masui 1994;43: 1727–36
37. Sato A, Sato Y, Schmidt RF. Heart rate changes reflecting modifications of efferent cardiac sympathetic outflow by cutaneous and muscle afferent volleys. J Auton Nerv Syst 1981;4:231–47