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

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.

GPR54-dependent stimulation of luteinizing hormone secretion by neurokinin B in prepubertal rats.

Kisspeptin, neurokinin B (NKB) and dynorphin A (Dyn) are coexpressed within KNDy neurons that project from the hypothalamic arcuate nucleus (ARC) to GnRH neurons and numerous other hypothalamic targets. Each of the KNDy neuropeptides has been implicated in regulating pulsatile GnRH/LH secretion. In isolation, kisspeptin is generally known to stimulate, and Dyn to inhibit LH secretion. However, the NKB analog, senktide, has variously been reported to inhibit, stimulate or have no effect on LH secretion. In prepubertal mice, rats and monkeys, senktide stimulates LH secretion. Furthermore, in the monkey this effect is dependent on kisspeptin signaling through its receptor, GPR54. The present study tested the hypotheses that the stimulatory effects of NKB on LH secretion in intact rats are mediated by kisspeptin/GPR54 signaling and are independent of a Dyn tone. To test this, ovarian-intact prepubertal rats were subjected to frequent automated blood sampling before and after intracerebroventricular injections of KNDy neuropeptide analogs. Senktide robustly induced single LH pulses, while neither the GPR54 antagonist, Kp-234, nor the Dyn agonist and antagonist (U50488 and nor-BNI, respectively) had an effect on basal LH levels. However, Kp-234 potently blocked the senktide-induced LH pulses. Modulation of the Dyn tone by U50488 or nor-BNI did not affect the senktide-induced LH pulses. These data demonstrate that the stimulatory effect of NKB on LH secretion in intact female rats is dependent upon kisspeptin/GPR54 signaling, but not on Dyn signaling.