Dr Volker Hoellt & Dr Horace H. Loh - 2007

"Regulation of opioid peptides and opioid receptors"

Dr. Volker Hoellt (on the right in picture below)
Otto-von-Guericke-Universitat Magdeburg 
Magdeburg, Germany

The lecture will cover several aspects of the regulation of opioid peptides and opioid receptors. Early attempts to identify alterations in the release of opioid peptides, peptide processing and biosynthesis in response to various physiological and pharmacological stimuli will be presented. With the aim to understand opioid tolerance, a variety of experiments designed to analyse the regulation of opioid receptors in response to opioid treatment will be shown. Starting with early trials to detect changes in the number of opioid receptor binding sites, the regulation of opioid receptors will be shown at the transcriptional level. In addition, the trafficking of opioid receptors in response to opioid agonists and its implication for opioid desensitization/tolerance will be shown. Finally, studies analysing functional variants of opioid receptors and opioid peptides and their relation to drug addiction will be presented.


"Our search for the 'Ideal Analgesic' in pain treatment"

Dr. Horace H. Loh (on the left in picture)

Frederick Stark Professor & Head
Department of Pharmacology
University of Minnesota
Minneapolis, MN, USA

It is well know that among all the drugs used in pain management, opioid analgesics are the most efficacious in controlling moderate and severe postoperative pain – but with accompanying adverse effects such as respiratory depression, constipation, nausea and addiction, that are concerns surrounding the continuous use of opioid drugs. Decades of research have focused on designing an opioid analgesic that has the efficacy of morphine but is devoid of morphine’s adverse effects – to make an “ideal analgesic”.

With the cloning of multiple opioid receptors and subsequent gene knockout studies, it is now known that the analgesic action of opioid agonist (such as morphine) is mediated via the μ-opioid receptor (MOR). Opioid antagonists (such as naloxone) which blocks the effect of an agonist via its interact at the MOR, but possesses no efficacy by itself.

In our original studies to determine the functional domain of MOR, we have found that mutation of a conserved serine in transmembrane region (TM)-4 of all opioid receptors confers agonistic properties to classical antagonists (PNAS. 93: 5715–5719, 1996). In other words, the observed agonists properties by an antagonist was due to the mutations of the conserved serine to leucne (or ala) in the fourth TM domain (S196L). To determine the pharmacological significance of this mutation, in vivo, we have used homologous recombination gene-targeting strategy and have introduced the MOR-S196A mutants into the mouse MOR gene by a knock-in strategy. In the homozygous mice, opioid antagonists such as naloxone, naltrexone elicited antinociceptive effects same as the agonists. More importantly, chronic treatment of these mice with antagonists did not produce the expected tolerance and physical dependence associated with morphine treatment (PNAS.100:2117–2121, 2003).

In order to test the feasibility of utilizing such receptor mutations in the treatment of chronic pain; our recent works have shown preliminary success by using gene therapy approaches. Using a well-defined delivery vehicle, we are able to see the expression of this mutant receptor in the nociceptive neurons of the proper segment of the spinal cord. By systemic administration of opioid antagonists, which devoid of opioid side effects, activation of this mutant MOR occurred while the endogenous wild type MOR were not activated. These results have provided a “proof of principal” that this should be a feasible approach to make an “ideal pain killing paradigm” for treatment of chronic pain.

Supported by grants from NIDA USA and NHRI; NSC of R.O.C.

INRC Conference