75 years of opioid research: the exciting but vain quest for the Holy Grail

Abstract

Over the 75-year lifetime of the British Pharmacological Society there has been an enormous expansion in our understanding of how opioid drugs act on the nervous system, with much of this effort aimed at developing powerful analgesic drugs devoid of the side effects associated with morphine--the Holy Grail of opioid research. At the molecular and cellular level multiple opioid receptors have been cloned and characterised, their potential for oligomerisation determined, a large family of endogenous opioid agonists has been discovered, multiple second messengers identified and our understanding of the adaptive changes to prolonged exposure to opioid drugs (tolerance and physical dependence) enhanced. In addition, we now have greater understanding of the processes by which opioids produce the euphoria that gives rise to the intense craving for these drugs in opioid addicts. In this article, we review the historical pathway of opioid research that has led to our current state of knowledge.

Figure 1

Extracting the juice from the opium poppy. Taken from ‘Opiologia' a treatise concerning the nature, properties, true preparation and safe use and administration of opium. Sala (Angelus) 1618. Wellcome History of Medicine Library.

Figure 2

Hans Walter Kosterlitz (1903–1996), the doyen of British opioid pharmacologists. Photograph courtesy of Alan North.

Figure 3

First demonstration that the μ-receptor couples to activation of a potassium conductance. Membrane hyperpolarisations of guinea-pig myenteric neurones in response to normorphine (Nor) and levorphanol (Lev), but not to dextrorphan (Dex). The response to normorphine was reversed by coapplication of naloxone (Nal) (North & Tonini, 1979, with permission).

Figure 4

Chemical template of morphine-related drugs illustrating the progressive simplification of the structure.