Josephine Lai

Professor of Pharmacology and Molecular and Cellular Biology
Ph.D., Imperial College, University of London, 1985

Life Sciences North 563
(520) 626-2147
lai@u.arizona.edu

Research Interests

• Molecular Mechanisms of Neuropathic Pain
  
• Opioid Receptor Pharmacology
  
• Gene Targeting
  
• Drug Discovery
  

Technical Expertise: Cellular and Molecular Neuropharmacology

• Radioligand binding analysis
  
• Functional assays for G-protein coupled receptors
  
• Immunohistochemistry, Western, EIA, RIA
  
• In situ hybridization; chromatographic and autoradiographic
  
• Fluorescence ratiometric imaging
  
• Cell culture; in vitro gene expression
  
• Antisense strategies in vivo and in vitro; siRNA
  
• Recombinant DNA techniques, RT-PCR
  

Highlight of Our Research

Spinal Dynorphin and Neuropathic Pain
Dynorphin is a neuropeptide that has unusual properties. It is structurally and pharmacologically defined as an endogenous opioid peptide that inhibits neuronal activity, yet at higher doses it is excitotoxic and induces long lasting abnormal pain. We have extensively characterized the neuronal excitatory actions of dynorphin by pharmacological, physiological and anatomical approaches, and are leaders in the elucidation of the mechanisms of action of dynorphin in chronic pain. The significance of these studies hopefully will pave the way to new therapeutics for the treatment of chronic pain based on dynorphin and its receptors as therapeutic targets.

Fig.1. Real-time analysis of intracellular calcium in a sensory neuron cell line by Fura-2 fluorescence microscopy. Left panel: baseline; Center panel: after adding agonist to the medium; Right panel: after adding potassium chloride to the medium. Color shift from blue to green depicts increase in calcium in individual cells. Graph traces the transient change in calcium in individual cells over time after drug addition.

Sodium Channels and Neuropathic Pain
Sodium channel activity is fundamental to the function of all neurons. Abnormal activity of these channels is critical to the development of chronic pain upon nerve injury. The utility of sodium channel blockers in chronic pain management is limited by severe side effects. We have established compelling evidence that one of the sodium channel sub-types, NaV1.8, is a potential therapeutic target as a selective blockade of this channel is sufficient to block abnormal pain. Because its expression is restricted to peripheral sensory neurons, drugs that are selective blockers for this channel should be effective with no central side effects.

Fig.2. Antisense oligonucleotide (ODN) mediated reversal of abnormal pain in nerve-injured rats. AS: antisense ODN; MM: mismatch ODN control. (Lai et al., Pain 95:143-52, 2002)

Selected Publications

Lai J, Porreca F, Hunter JC, Gold MS (in press) Voltage-gated sodium channels and hyperalgesia. Ann. Rev. Pharmacol. Toxicol.

Gardell LR, Ibrahim M, Wang R, Wang Z, Ossipov MH, Malan, TP, Jr., Porreca F, Lai J (in press) Mouse strains that lack spinal dynorphin upregulation after peripheral nerve injury do not develop neuropathic pain. Neurosci.

Wang R, Guo W, Ossipov MH, Vanderah TW, Porreca F, Lai J (in press) GDNF normalizes neurochemical changes in injured dorsal root ganglion neurons and prevents the expression of experimental neuropathic pain. Neurosci.

Gold MS, Weinreich D, Kim CS, Wang R, Porreca F, Lai J (2003) Redistribution of NaV1.8 in uninjured axons enables neuropathic pain. J. Neurosci. 23:158-166.

Lai J, Hunter JC, Porreca F (2003) The role of voltage-gated sodium channels in neuropathic pain. Curr Opin Neurobiol, 13:291-297.

M-c Luo, D-q Zhang, S-w Ma, Y-y Huang, SJ Shuster, F Porreca and J Lai
An efficient intrathecal delivery of small interfering RNA to the spinal cord and peripheral neurons Mol Pain 1:29, 2005.

MM Ibrahim, F Porreca, J Lai, PJ Albrecht, FL Rice, A Khodorova, G Davar, A Makriyannis, TW Vanderah, HP Mata, TP Malan, Jr. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci (USA) 102:3093-8, 2005.

RS Agnes, YS Lee, P Davis, S-w Ma, H Badghisi, F Porreca, J Lai, and VJ Hruby
Structure activity relationships of bifunctional peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors. J Med Chem 49: 2868-2875, 2006.

VJ Hruby, F Porreca, HI Yamamura, G Tollin, RS Agnes, YS Lee, M Cai, I Alves, S Cowell, E Navratilova, P Davis, Z Salamon, W Roeske, TW Vanderah, J Lai
"New Paradigms and Tools in Drug Design for Pain and Addiction" NIDA-AAPS Proceedings (in press).

J Lai, M-c Luo, Q Chen, S-w Ma, LR Gardell, MH Ossipov, F Porreca
Dynorphin A activates bradykinin receptors to maintain neuropathic pain. Nature Neuroscience (in press)