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Neurourology Research Laboratory
Harrison Department of Surgical Research
Anna P. Malykhina, Ph.D.
 

Our research interests center on neurophysiology of the lower urinary tract (LUT) and functional chronic pelvic pain disorders, with particular emphasis on the mechanisms underlying the processing of sensory nociceptive information by the central and peripheral nervous systems. Additional areas of interest include neurogenic bladder dysfunctions, neuropathic pain, and mechanosensitivity of the overactive bladder.

  1. Neural mechanisms of pelvic organ cross-sensitization and chronic pelvic pain  

Clinical observations of viscerovisceral referred pain and hyperalgesia in patients with gastrointestinal and/or genitourinary disorders are well documented. Chronic pelvic pain is a major symptom of many complex clinical conditions, including painful bladder syndrome (PBS), non-bacterial chronic prostatitis, irritable bowel syndrome (IBS), vulvodynia. Pelvic organ cross-sensitization is considered to be one of the factors contributing to chronic pelvic pain of unidentified origin. Cross-sensitization in the pelvis implies the transmission of noxious stimuli from a diseased pelvic organ to an adjacent normal structure resulting in the occurrence of functional (rarely structural) changes in the latter. Distribution of sensitization in the pelvis mainly occurs via shared sensory neural pathways at prespinal, spinal and supraspinal levels (reviewed in Malykhina A.P.Neural mechanisms of pelvic organ cross-sensitization (2007). Neuroscience, Review). We use neuroanatomical, immunohistochemical, electrophysiological and neuropharmacological methods to characterize the role of sensory neural pathways in cross-sensitization between pelvic organs and chronic pelvic pain. This work is supported by the NIH/NIDDK R01 grant DK077699.

  1. Neurogenic bladder dysfunctions in neurological disorders

Neurogenic bladder dysfunctions often occur in patients with neurological disorders such as multiple sclerosis, Parkinson`s disease, Alzheimer`s disease, amyotrophic lateral sclerosis.  Bladder symptoms present in 32–97% of patients with neurological disorders. They include urinary urgency, urinary incontinence, nocturia, urinary hesitancy, overflow incontinence, a sensation of incomplete emptying, frank urinary retention and a weak urinary stream. It is thought that neurogenic bladder dysfunction develops due to lesions in the brain and/or spinal cord or from loss of axons from the pathways that control bladder function. In approximately 5–10% of patients, bladder symptoms are present at the onset of multiple sclerosis when there may be few lesions identified in the spinal cord and/or brain. In patients with established MS, bladder symptoms are prevalent and often associated with symptoms of bowel and sexual dysfunction. This research is currently supported by P20 grant from the NIDDK (DK097819) and is a part of the Philadelphia Center on Interdisciplinary Research in Benign Urology (IR-BU) Program (PI- Anna Malykhina)

  1. Mechanisms of mechanotransduction in the detrusor smooth muscle in OAB

Mechanosensitivity of the detrusor is defined as the ability of smooth muscle cells to generate mechanical activity independent of external stimuli. Activation of mechanosensitive receptors on smooth muscle cells is a first step in initiating mechanotransduction in the bladder wall with subsequent transmission of the signal to sensory neurons and, further, to the CNS. Pathological changes in bladder mechanotransduction lead to the development of detrusor overactivity (DO) which is a co-symptom of several dysfunctions of the lower urinary tract including overactive bladder, obstructed bladder, diabetic overactivity, urinary incontinence, bladder pain syndrome.  This project is focused on the mechanisms of impaired mechanosensation and mechanotransductionwhich  may underlie detrusor overactivity due to alterations in mechanotransduction between bladder smooth muscle cells and intrinsic nerve fibers in the bladder wall. 

  1. Modulation of pelvic pain by ovarian  hormones in neurogenic cystitis

Interstitial Cystitis or Painful Bladder Syndrome (IC/PBS) is a debilitating medical condition characterized by chronic pelvic pain (CPP), pressure and discomfort related to the urinary bladder accompanied by persistent urge to void and urinary frequency. While both men and women suffer from this painful disorder, there is significantly higher rate of IC/PBS in women with a female to male ratio in the 4.5 to 9 times range.  Ovarian hormones may modulate pain thresholds and/or pain tolerance in females. The goal of this project is to investigate the effects of ovarian hormones and their role in the pathophysiology of neurogenic IC/PBS in women.

Technical Approaches include survival rodent surgeries, use of retrograde fluorescent tracers, immunohistochemistry, in vivo and in vitro contractility studies, patch clamp and microelectrode techniques, primary neuronal and smooth muscle cell culture, ELISA, Western blotting, conventional and quantitative RT-PCR.

Keywords: Chronic pelvic pain, functional pelvic syndromes, neurogenic bladder dysfunctions, sensory pathways, dorsal root ganglion neurons, ion channels, neuropeptides and growth factors, neurogenic cystitis,smooth muscle pathophysiology.

 
Selected Publications
  1. Lei Q., Malykhina A.P. (2012) Colonic inflammation up-regulates voltage-gated sodium channels in bladder sensory neurons via activation of peripheral transient potential vanilloid 1 receptors. Neurogastroenterology and Motility Jun;24(6):575-e257.
  2. Malykhina A.P., Wyndaele J.J., Andersson K.-E., de Wachter S., Dmochowski R.R. (2012) Do the urinary bladder and large bowel interact, in sickness or in health? Neurourology Urodynamics Mar;31(3):352-8.
  3. Cory L., Harvie H.S., Northington G.M., Malykhina A., Whitmore K., Arya L.A. (2012) Association of neuropathic pain with bladder, bowel and catastrophizing symptoms in women with bladder pain syndrome. J Urol, Feb;187(2):503-7.
  4. Arya LA, Northington G.M., Asfaw T.S., Harvie H., Malykhina A. (2012) Evidence of bladder oversensitivity in the absence of an infection in premenopausal women with a history of recurrent urinary tract infections. BJU Int Nov 30 
  5. Asfaw T.S., Hypolite J., Northington G.M., Arya L.A., Wein A.J., Malykhina A.P. (2011) Acute colonic inflammation triggers detrusor instability via activation of TRPV1 receptors in a rat model of pelvic organ cross-sensitization Am J Physiol Regul Integr Comp Physiol.300: R1392–1400.
  6. Pan X.-Q., Gonzalez J.A., Chang S., Chacko S, Wein A., Malykhina A.P. (2010) Experimental colitis triggers the release of substance P and calcitonin gene-related peptide in the urinary bladder via TRPV1 signaling pathways. Exp Neurology. 225(2):262-73.
  7. Qin C., Malykhina A.P., Thompson A, Farber J, Foreman R.D. (2010) Cross-organ sensitization of thoracic spinal neurons receiving noxious cardiac input in rats with gastroesophageal reflux. Am J Physiol Gastrointest Liver Physiol. 298(6):G934-42.
  8. Malykhina A.P. (2007) Neural mechanisms of pelvic organ cross-sensitization. Neuroscience. Review. 149(3):660-672.
  9. Noronha R., Akbarali H.I., Malykhina A.P., Foreman R.D., Greenwood-Van Meerveld B. (2007) Changes in urinary bladder smooth muscle function in response to colonic inflammation. Am J Physiol Renal Physiol,  293(5):F1461-F1467.
  10. Clark R.M., De Biase I., Malykhina A.P., Al-Mahdawi S., Pook M. and Bidichandani S.I. (2007) The GAA triplet-repeat is unstable in the context of the human FXN locus and displays age-dependent expansions in cerebellum and DRG in a transgenic mouse model.  Hum Genet.,120(5):633-40.
  11. Malykhina A.P., Qin C., Greenwood-van Meerveld B., Foreman R.D., Lupu F., Akbarali H. (2006) Hyperexcitability of convergent colon and bladder dorsal root ganglion neurons after colonic inflammation: mechanism for pelvic organ cross-talk. Neurogastroenterol Motil 18:936-948.
  12. Qin C., Malykhina A.P., Akbarali H.I. and Foreman R.D. (2005) Cross-organ sensitization of lumbosacral spinal neurons receiving urinary bladder input in rats with inflamed colon. Gastroenterology, 129(6):1967-1978.
  13. Malykhina A.P., Qin C., Foreman R.D., Akbarali H.I. (2004) Colonic inflammation increases Na+ currents in bladder sensory neurons. Neuroreport. 15(17): 2601-2605.
  14. Malykhina A.P. and Akbarali H.I. (2004) Inflammation-induced “channelopathies” in gastrointestinal smooth muscle. Cell Biochem. Biophys. 41:319-330 (Invited review).
  15. Shoeb F.*, Malykhina A.P.*, Akbarali H.I. (2003) Cloning and functional characterization of the smooth muscle ether-a-go-go related gene K+ channel: Potential role of a conserved amino acid substitution in the S4 region. J Biol Chem. Jan 24; 278(4):2503-14. *-equal contribution
  16. Malykhina A.P., Shoeb F., Akbarali H.I. (2002) Fenamate-induced enhancement of heterologously expressed HERG current in Xenopus oocytes. Eur. J. Pharm. Oct 11;452(3):269-277 .

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