Sandra P. Welch, Ph.D.
- Virginia Commonwealth University, 1986
- Cellular pharmacology
- Role of free intracellular calcium in tolerance and physical dependence to drugs of abuse
- Endocrine modulation of tolerance
- Second messengers
One major interest in this laboratory is the regulation of the release of endogenous opioid peptides by the cannabinoids, alone and in combination with morphine and other opiates. We have demonstrated that the cannabinoids are potent antinociceptive drugs. We are now investigating the underlying mechanisms for such effects. We have recently demonstrated that cannabinoids release the endogenous opioid dynorphin at the spinal cord level. In addition, we have shown that cannabinoids alter both calcium and c-AMP levels in the release of dynorphin. The role of anandamide, an endogenous cannabinoid, in pain is also under investigation. Anandamide appears to lack an interaction with the endogenous opioids, unlike the other cannabinoids evaluated. We are currently evaluating the mechanisms underlying the antinociceptive effects of anandamide using behavioral, biochemical and molecular approaches.
A second major goal of this laboratory is to determine the mechanisms underlying the development of tolerance to morphine and other opioids. We have shown that tolerance to the opioids involves an increase in intracellular calcium concentrations. Using neuropharmacological and molecular techniques, we have demonstrated recently that the mu opioid receptor is dephosphorylated and down-regulated following the chronic administration of morphine to mice. This effect is the opposite of that observed upon acute administration of morphine and may represent a compensatory mechanism in tolerance to opioids.
In addition, we have shown that ATP-gated potassium channels are increased in number in morphine-tolerant mice. Current studies include evaluation of calcium channel subunit proteins using western immunoblotting, immunoprecipitation and back-phosphorylation techniques. Opioid peptide release directly from the spinal cord is being quantitated using spinal cord perfusion followed by radioimmunoassay for the peptides. Our studies will hopefully lead to the development of novel analgesic agents for use at the spinal level in the treatment of acute and chronic pain.
Sim-Selley LJ, Goforth PB, Mba MU, Macdonald TL, Lynch KR, Milstien S, Spiegel S, Satin LS, Welch SP and Selley DE. (2009) Sphingosine-1-phosphate receptors mediate neuromodulatory functions in the CNS. Journal of Neurochemistry. 110(4):1191-202.
Welch SP. (2009) Interaction of the cannabinoid and opioid systems in the modulation of nociception. International Review of Psychiatry. 21(2):143-51.
Haller VL, Stevens DL and Welch SP. (2008) Modulation of opioids via protection of anandamide degradation by fatty acid amide hydrolase. European Journal of Pharmacology. 600(1-3):50-8.
Williams J, Haller VL, Stevens DL and Welch SP. (2008) Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception. European Journal of Pharmacology. 584(1):78-86.