Delayed Behavioral Effects of SH–I–048A, a Novel Nonselective Positive Modulator of Gabaa Receptors, After Peripheral Nerve Injury in Rats

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The complex clinical picture of mono-neuropathy following injury of peripheral nerve is often accompanied by changes in the patients’ affective states. It has been shown that positive allosteric modulators of GABAA receptors can decrease nociceptive transmission in animal pain models. However, recent findings suggest a possibility that at least some of the antinociceptive effects of benzodiazepines, related to neuropathic painful stimuli, may to a significant degree be a consequence of their anxiolytic action.

In this study we evaluated the possible delayed effects of SH-I-048A, a newly- synthesized high-efficacy nonselective positive modulator of GABAA receptors, on anxiety-like behavior and locomotor activity in Wistar rats with a previously induced peripheral nerve injury.

Assessment of behavioral parameters, using spontaneous locomotor activity and elevated plus maze tests, was performed 48h after completion of single-day threei. p. injections treatment consisting of zero, one, two or three doses of SH-I-048А (10 mg/kg).

In general, rats’ behavior observed 72 h after a moderate peripheral nerve injury did not indicate the persistence of sequelae of mono-neuropathic pain. The rats treated with three doses of SH-I-048А displayed an enhanced immobility time in the locomotor activity test, without concomitant decrease of the total distance traveled. On the other hand, in the group treated with two doses of SH- I-048А, a decrease in the emotional reactivity in the elevated plus maze test was observed. Subtle changes in the regimen of dosing of SH-I-048А affect locomotor activity and anxiety-related behavior in animals with peripheral nerve injury.

1. Gormsen L, Rosenberg R, Bach FW, Jensen TS: Depression, anxiety, health-related quality of life and pain in patients with chronic fibromyalgia and neuropathic pain. Eur J Pain 2010, 14:127.e1-8.

2. Munro G, Ahring PK, Mirza NR: Developing analgesics by enhancing spinal inhibition after injury: GABAA receptor subtypes as novel targets. Trends Pharmacol Sci 2009, 30:453-9.

3. Knabl J, Zeilhofer UB, Crestani F, Rudolph U, Zeilhofer HU: Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABAA receptor point-mutated mice. Pain 2009, 141:233-8.

4. Malan TP, Mata HP, Porreca F: Spinal GABA(A) and GABA(B) receptor pharmacology in a rat model of neuropathic pain. Anesthesiology 2002, 96:1161-7.

5. Casarrubea M, Sorbera F, Santangelo A, Crescimanno G: The effects of diazepam on the behavioral structure of the rat’s response to pain in the hot-plate test: anxiolysis vs. pain modulation. Neuropharmacology 2012, 63:310-21.

6. Stahl SM: Don’t ask, don’t tell, but benzodiazepines are still the leading treatments for anxiety disorder. J Clin Psychiatry 2002, 63:756-7.

7. Sieghart W, Ernst M: Heterogeneity of GABAA receptors: revived interest in the development of subtype-selective drugs. Curr Med Chem - Central Nervous System Agents 2005, 5:217-242.

8. Auta J, Kadriu B, Giusti P, Costa E, Guidotti A. Anticonvulsant, anxiolytic, and non- sedating actions of imidazenil and other imidazo-benzodiazepine carboxamide derivatives. Pharmacol Biochem Behav 2010, 95:383-9.

9. Rabe H, Kronbach C, Rundfeldt C, Lüddens H: The novel anxiolytic ELB139 displays selectivity to recombinant GABA(A) receptors different from diazepam. Neuropharmacology 2007, 52:796-801.

10. Rudolph U, Crestani F, Benke D, Brünig I, Benson JA, Fritschy JM, Martin JR, Bluethmann H, Möhler H: Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature 1999, 401:796-800.

11. McKernan RM, Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, et al: Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype. Nat Neurosci 2000, 3:587-92.

12. Knabl J, Witschi R, Hösl K, Reinold H, Zeilhofer UB, Ahmadi S, et al: Reversal of pathological pain through specific spinal GABAA receptor subtypes. Nature 2008, 451:330-4.13.

13. Cook JM, Huang S, Sarma PVVS, Zhang C, Zhou H; Wisys Technology Found Inc, James M Cook, Hao Zhou, Shengming Huang, P V V S Sarma, Chunchun Zhang, assignee. Stereospecific anxiolytic and anticonvulsant agents with reduced muscle-relaxant, sedativehypnotic and ataxic effects. United States patent US WO2006004945 A1 2006 Jan 12. []

14. Drexler B, Zinser S, Huang S, Poe MM, Rudolph U, Cook JM, Antkowiak B: Enhancing the function of alpha5-subunit-containing GABAA receptors promotes action potential firing of neocortical neurons during up-states. Eur J Pharmacology 2013, 5:703.

15. Gill KM, Lodge DJ, Cook JM, Aras S, Grace AA: A novel α5GABA(A)R-positive allosteric modulator reverses hyperactivation of the dopamine system in the MAM model of schizophrenia. Neuropsychopharmacology 2011, 36:1903-11.

16. Bridge PM, Ball DJ, Mackinnon SE, Nakao Y, Brandt K, Hunter DA, et al: Nerve crush injuries--a model for axonotmesis. Exp Neurol 1994, 127:284-90.

17. Savić MM, Huang S, Furtmüller R, Clayton T, Huck S, Obradović DI, et al: Are GABAA receptors containing alpha5 subunits contributing to the sedative properties of benzodiazepine site agonists? Neuropsychopharmacology 2008, 33:332-9.

18. Savić MM, Majumder S, Huang S, Edwankar RV, Furtmüller R, Joksimović S, et al: Novel positive allosteric modulators of GABAA receptors: do subtle differences in activity at alpha1 plus alpha5 versus alpha2 plus alpha3 subunits account for dissimilarities in behavioral effects in rats? Prog Neuropsychopharmacol Biol Psychiatry 2010, 34:376-86.

19. Savić MM, Obradović DI, Ugresić ND, Cook JM, Yin W, Bokonjić DR: Bidirectional effects of benzodiazepine binding site ligands in the elevated plus-maze: differential antagonism by flumazenil and beta-CCt. Pharmacol Biochem Behav 2004, 79:279-90.

20. Dworkin RH: An overview of neuropathic pain: syndromes, symptoms, signs, and several mechanisms. Clin J Pain 2002, 18:343-9.

21. Finnerup NB, Sindrup SH, Jensen TS: The evidence for pharmacological treatment of neuropathic pain. Pain 2010, 150:573-81.

22. O’Connor AB, Dworkin RH: Treatment of neuropathic pain: an overview of recent guidelines. Am J Med 2009, 122:S22-32.

23. Ellis A, Bennett DL: Neuroinflammation and the generation of neuropathic pain. Br J Anaesth 2013, 111:26-37.

24. Naik AK, Latham JR, Obradovic A, Jevtovic-Todorovic V: Dorsal root ganglion application of muscimol prevents hyperalgesia and stimulates myelin protein expression after sciatic nerve injury in rats. Anesth Analg 2012, 114:674-82.

25. Huston JP, Schulz D, Topic B: Toward an animal model of extinction-induced despair: focus on aging and physiological indices. J Neural Transm 2009, 116:1029-36.

26. Ryan CG, Gray HG, Newton M, Granat MH: The relationship between psychological distress and free-living physical activity in individuals with chronic low back pain. Man Ther 2010, 15:185-9.

27. Divljaković J, Milić M, Timić T, Savić MM: Tolerance liability of diazepam is dependent on the dose used for protracted treatment. Pharmacol Rep 2012, 64:1116-25.

28. Friedman H, Abernethy DR, Greenblatt DJ, Shader RI: The pharmacokinetics of diazepam and desmethyldiazepam in rat brain and plasma. Psychopharmacology 1986, 88:267-70.

29. Samardžić J, Puškaš L, Obradović M, Lazić-Puškaš D, Obradović D: Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test, Acta Vet (Beograd) 2014, 64(1):52-60.

Acta Veterinaria

The Journal of University of Belgrade

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