Systemic and Intrathecal Baclofen Produce Bladder Antinociception in Rats

Overview

Journal BMC Urol

Publisher Biomed Central

Specialty Urology

Date 2021 Oct 5

PMID 34607587

Authors

Timothy J Ness

Alan Randich

Xin Su

Cary DeWitte

Keith Hildebrand

Affiliations

Soon will be listed here.

Abstract

Background: Baclofen, a clinically available GABA receptor agonist, produces non-opioid analgesia in multiple models of pain but has not been tested for effects on bladder nociception.

Methods: A series of experiments examined the effects of systemic and spinally administered baclofen on bladder nociception in female anesthetized rats. Models of bladder nociception included those which employed neonatal and adult bladder inflammation to produce bladder hypersensitivity.

Results: Cumulative intraperitoneal dosing (1-8 mg/kg IP) and cumulative intrathecal dosing (10-160 ng IT) of baclofen led to dose-dependent inhibition of visceromotor responses (VMRs) to urinary bladder distension (UBD) in all tested models. There were no differences in the magnitude of the analgesic effects of baclofen as a function of inflammation versus no inflammation treatments. Hemodynamic (pressor) responses to UBD were similarly inhibited by IT baclofen as well as UBD-evoked excitatory responses of spinal dorsal horn neurons. The GABA receptor antagonist, CGP 35,348, antagonized the antinociceptive effects of IT baclofen on VMRs in all tested models but did not affect the magnitude of the VMRs by itself suggesting no tonic GABA activity was present in this preparation. Tolerance to a seven day continuous IT infusion of baclofen was not observed.

Conclusions: These data provide support for a clinical trial of baclofen as a non-opioid treatment of human bladder pain.

References

Kontani H, Kawabata Y, KOSHIURA R . The effect of baclofen on the urinary bladder contraction accompanying micturition in anesthetized rats. Jpn J Pharmacol. 1988; 46(1):7-15. DOI: 10.1254/jjp.46.7. View

Aley K, Kulkarni S . Baclofen analgesia in mice: a GABAB-mediated response. Methods Find Exp Clin Pharmacol. 1991; 13(10):681-6. View

Saulino M . Simultaneous treatment of intractable pain and spasticity: observations of combined intrathecal baclofen-morphine therapy over a 10-year clinical experience. Eur J Phys Rehabil Med. 2011; 48(1):39-45. View

Randich A, Mebane H, Ness T . Ice water testing reveals hypersensitivity in adult rats that experienced neonatal bladder inflammation: implications for painful bladder syndrome/interstitial cystitis. J Urol. 2009; 182(1):337-42. DOI: 10.1016/j.juro.2009.02.107. View

Enna S, Harstad E, McCarson K . Regulation of neurokinin-1 receptor expression by GABA(B) receptor agonists. Life Sci. 1998; 62(17-18):1525-30. DOI: 10.1016/s0024-3205(98)00101-5. View

Kontani H, Ueda Y . A method for producing overactive bladder in the rat and investigation of the effects of GABAergic receptor agonists and glutamatergic receptor antagonists on the cystometrogram. J Urol. 2005; 173(5):1805-11. DOI: 10.1097/01.ju.0000154345.87935.a4. View

Sillen U, Persson B, Rubenson A . Central effects of baclofen on the L-dopa induced hyperactive urinary bladder of the rat. Naunyn Schmiedebergs Arch Pharmacol. 1985; 330(3):175-8. DOI: 10.1007/BF00572430. View

Boster A, Adair R, Gooch J, Nelson M, Toomer A, Urquidez J . Best Practices for Intrathecal Baclofen Therapy: Dosing and Long-Term Management. Neuromodulation. 2016; 19(6):623-31. DOI: 10.1111/ner.12388. View

Dirig D, Yaksh T . Intrathecal baclofen and muscimol, but not midazolam, are antinociceptive using the rat-formalin model. J Pharmacol Exp Ther. 1995; 275(1):219-27. View

10.

Paterson N, Froestl W, Markou A . The GABAB receptor agonists baclofen and CGP44532 decreased nicotine self-administration in the rat. Psychopharmacology (Berl). 2003; 172(2):179-86. DOI: 10.1007/s00213-003-1637-1. View

11.

Chen C, Meng E . Can Botulinum Toxin A Play A Role In Treatment Of Chronic Pelvic Pain Syndrome In Female Patients?-Clinical and Animal Evidence. Toxins (Basel). 2020; 12(2). PMC: 7076794. DOI: 10.3390/toxins12020110. View

12.

Kent C, Park C, Lindsley C . Classics in Chemical Neuroscience: Baclofen. ACS Chem Neurosci. 2020; 11(12):1740-1755. DOI: 10.1021/acschemneuro.0c00254. View

13.

Talalla A, Grundy D, Macdonell R . The effect of intrathecal baclofen on the lower urinary tract in paraplegia. Paraplegia. 1990; 28(7):420-7. DOI: 10.1038/sc.1990.56. View

14.

Jasmin L, Rabkin S, Granato A, Boudah A, Ohara P . Analgesia and hyperalgesia from GABA-mediated modulation of the cerebral cortex. Nature. 2003; 424(6946):316-20. DOI: 10.1038/nature01808. View

15.

Chen C, Tyagi P, Chuang Y . Promise and the Pharmacological Mechanism of Botulinum Toxin A in Chronic Prostatitis Syndrome. Toxins (Basel). 2019; 11(10). PMC: 6832516. DOI: 10.3390/toxins11100586. View

16.

Assadi S, Radgoodarzi R, Ahmadi-Abhari S . Baclofen for maintenance treatment of opioid dependence: a randomized double-blind placebo-controlled clinical trial [ISRCTN32121581]. BMC Psychiatry. 2003; 3:16. PMC: 293465. DOI: 10.1186/1471-244X-3-16. View

17.

Heetla H, Staal M, van Laar T . Tolerance to continuous intrathecal baclofen infusion can be reversed by pulsatile bolus infusion. Spinal Cord. 2009; 48(6):483-6. DOI: 10.1038/sc.2009.156. View

18.

Harmer J, Larson B . Pain relief from baclofen analgesia in a neuropathic pain patient who failed opioid and pharmacotherapy: case report. J Pain Palliat Care Pharmacother. 2003; 16(3):61-4. DOI: 10.1080/j354v16n03_06. View

19.

Grinberg K, Weissman-Fogel I, Lowenstein L, Abramov L, Granot M . How Does Myofascial Physical Therapy Attenuate Pain in Chronic Pelvic Pain Syndrome?. Pain Res Manag. 2020; 2019:6091257. PMC: 6930783. DOI: 10.1155/2019/6091257. View

20.

Adamian L, Urits I, Orhurhu V, Hoyt D, Driessen R, Freeman J . A Comprehensive Review of the Diagnosis, Treatment, and Management of Urologic Chronic Pelvic Pain Syndrome. Curr Pain Headache Rep. 2020; 24(6):27. DOI: 10.1007/s11916-020-00857-9. View