Peter M. Lalley

Professor (emeritus)

Contact Information
Email: pmlalley@wisc.edu
(608) 263-4697 Phone
(608) 265-5512 Fax

Research Interests
Neurohumoral control of the respiratory network

Current research in this laboratory is focused on how mu-type opioid receptors and D1- and D2-dopamine receptors affect membrane potential and discharge properties of medullary respiratory neurons , and how their neurohumoral actions influence ventilation.

Several types of measurements are made in vivo to detect neuronal and ventilatory responses to opioid and dopamine receptor ligands. Intracellular and extracellular recordings monitor membrane potential, membrane currents and discharge properties of medullary respiratory neurons. In parallel, respiratory motor nerve output is recorded from the phrenic nerve or from laryngeal motor nerves. Opioid and dopamine receptor ligands are administered by i.v. injection, topical application to the medulla, or by juxtacellular microelectrophoresis. Effects on ventilation are monitored by recording end-tidal CO2, tracheal pressure changes and effects on hemoglobin oxygen saturation and arterial pO2 and pCO2.

The opioid receptor studies have so far identified cellular sites of action and neuronal mechanisms that explain how clinically used opiates such as fentanyl can reduce tidal volume, slow breathing frequency, reduce chest wall compliance and increase upper airway resistance (see refs 1, 5, below).

Dopamine receptor studies have shown that D1- agonists increase membrane potential depolarization and discharge activity in medullary inspiratory neurons that control phrenic nerve motor output to the diaphragm and to the chest wall inspiratory muscles.

Application of SKF-38393, a highly selective D1-dopamine receptor agonist, to the surface of the medulla depolarizes membrane potential (MP) of a bulbospinal inspiratory neuron and increases discharge intensity and duration. SKF, 500 mM, was injected after control records were taken into a well positioned on the dorsal surface of the medulla over the location of inspiratory neurons in the Ventral Respiratory Column (Unpublished Results). Intracellular records were obtained in discontinuous constant current mode. Dashed lines in panels A and B denote control MP during periodic hyperpolarization, to illustrate the degree of depolarization (10 mV) produced by SKF. Regular downward deflections of MP in B were produced by 100 mS constant current pulses, in order to detect agonist effects on neuron input resistance (Rn). Traces in D are enlarged and time-expanded, showing that there was no change of Rn. The excitatory actions of SKF must therefore occur upstream on input neurons. Phrenic nerve (PNA) inspiratory discharges are also increased and prolonged by DHD, as shown by the superimposed control and treatment records in panel C. Intravenous administration of SKF evokes qualitatively identical effects (PM Lalley, Resp. Physiol. Neurobiol. 2004)

Phrenic nerve measurements taken while end-tidal CO2 is varied show that D1- agonists increase respiratory network responsiveness to CO2/pH (the primary chemical stimulus to breathe), and significantly reduce opiate depression of CO2 responsiveness (ref. 2).

Measurements of spontaneous breathing reveal that D1-agonists improve ventilation by increasing tidal volume and inspiratory duration (refs 4, 7). Of potential clinical significance, the agonists also reverse and prevent opiate depression of spontaneous breathing without compromising opiate analgesia (refs. 4,8).

The continuing objectives in studies from this laboratory will be to first identify neurohumoral agents and mechanisms that regulate the behavior of specific types of bulbar respiratory neurons, and then determine how the cellular effects influence ventilatory mechanics and gas exchange.

Selected Publications:

1. Lalley, P.M. mu-opioid receptor agonist effects of medullary respiratory neurons in the cat: evidence for involvement in certain types of ventilatory disturbances. Am. J. Physiol. Reg., Integ. and Comp. Physiol. 285: R1287-R1304 (2003).
    
2. Lalley. P.M. D1-Dopamine Receptor Agonists Reverse Respiratory Network Depression by Opioids, Increase Reactivity to CO2. Resp. Physiol. & Neurobiol. 139 : 247-262, 2004.
    
3. Lalley, P.M., D1-Dopamine receptor blockade slows respiratory rhythm and enhances opioid-mediated depression. Resp. Physiol. & Neurobiol. 145: 13-22, 2005
    
4. Lalley, P.M. D1-dopamine receptor agonists prevent and reverse opiate depression of breathing but not antinociception in the cat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 289:R45-51, 2005
    
5. Lalley, P.M. Opiate slowing of feline respiratory rhythm and effects on putative medullary phase-regulating neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290: R1387-96, 2006
    
6. Lalley, P.M. Opioidergic and dopaminergic modulation of respiration. Resp. Physiol. Neurobiol. 164: 160-167, 2008.
    
7. Lalley, P.M. The D1/D2-dopamine receptor agonist dihydrexdine stimulates inspiratory motor output and depresses medullary expiratory neurons. Am. J. Physiol. Regul. Integr. Comp. Physiol. In Press, March 2009
    
8. Lalley, P.M. Method of inducing opioid analgesia and anesthesia without respiratory suppression. P01356US, U.S. Patent No. 6,706,704. Expires Nov. 9, 2021.
    

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