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.

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1 The psychoactive cannabinoids (-)-A9-tetrahydrocannabinol ((-)-A9-THC) and the 1,l-dimethylheptyl homologue of (-)-11-hydroxy-A8-tetrahydrocannabinol ((-)-DMH) both inhibited electricallyevoked contractions of the mouse isolated vas deferens and the myenteric plexus-longitudinal muscle preparation of the guinea-pig small intestine. 2 Concentrations of (-)-A9-THC and (-)-DMH that decreased twitch heights by 50% were 6.3 and 0.15nM respectively in the mouse vas deferens and 60nM and 1.4nM respectively in the myenteric plexus preparation. (-)-DMH was about 40 times more potent than (-)-A9-THC in both preparations, supporting the notion that their mode of action in each tissue is the same. 3 The psychically inactive cannabinoid, (+)-DMH, had no inhibitory effect in the mouse vas deferens at a concentration of 30 nM, showing it to be at least 1000 times less potent than (-)-DMH. In the myenteric plexus preparation, (+)-DMH was about 500 times less potent than its (-)-enantiomer. 4 The inhibitory effects of sub-maximal concentrations of (-)-A9-THC were not attenuated by 300 nM naloxone. 5 The findings that (-)-A9-THC and (-)-DMH are highly potent as inhibitors of the twitch response of the mouse vas deferens and guinea-pig myenteric plexus preparation and that DMH shows considerable stereoselectivity suggest that the inhibitory effects of cannabinoids in these preparations are mediated by cannabinoid receptors.

Background-The most common form of CMT with slow nerve conduction velocities (CMT type I) is CMT1A, caused by a submicroscopic duplication of a region of DNA on chromosome 17 including the PMP22 gene. This gene is expressed in peripheral nerve but not in the CNS. The second most common form is CMTX, caused by mutations in the connexin32 gene in the X chromosome. Connexin32 is expressed both in brain and in peripheral nerve. These molecular variants are difficult to distinguish clinically. Methods-Brain stem auditory evoked responses (BAERs) were measured in patients with CTMX and CMT1A. Results-BAERs showed central conduction slowing in male patients with CMTX which did not overlap the normal range. Patients with CMT1A had a delay in wave I latency but otherwise normal responses. These results are consistent with the pattern of expression of PMP22 in the peripheral portion of the eighth nerve (myelinated by Schwann cells) and of connexin32 in the central portion in the brainstem auditory pathways (myelinated by oligodendrocytes). This is the first evidence for central involvement in CMTX. Conclusion-BAERs are useful to distinguish CMTX from CMT1A and may assist selection of appropriate patients for connexin32 mutation analysis.