Peptide Hormones of the Opiate System

Relief from pain has been an age-old aspiration of humankind. Natural substances— opium alkaloids from the latex of the poppy (Papaver somniferum, the sleep-bringing 

In 1974, Liebeskind showed the existence of a central pain-suppressive system, and was able to produce analgesia by electrical stimulation of the periventricular gray matter within the brain. This electroanalgesia could be reversed by opiate antagonists, and showed a cross-tolerance with morphine-induced analgesia. These results indicated the existence of a neuronal system that uses an endogenous neuromodulator or neurotransmitter with opiate-like properties. 

The isolation of such endogenous opiates was reported simultaneously by four laboratories those of Goldstein in Palo Alto, Hughes in Aberdeen, Snyder in Baltimore, and Terenius in Uppsala. Acetone extracts of pig, calf, and rat brains yielded, after purification, two pentapeptides, called enkephalins, with the structures NHj-Tyr-Gly-Gly-Phe-Met-COOH (5.83, Met-enkephalin) and NHj-Tyr-Gly-Gly-Phe-Leu-COOH (5.84, Leu-enkephalin). These are present in a 4 1 ratio in pig brain but in a 1 4 ratio in cattle 

2 Structure-Activity Correlations of Opioid Peptide Hormones 

There are various opioid receptors the three major classes of opioid receptors are mu (p), delta (5) and kappa (k) receptors. The p, receptor is the principal pain-modulating site in the CNS, mediating the action of morphine. There is considerable interest in the K receptor, which mediates a sedating analgesia with decreased addiction liability and respiratory depression and which allows for some structural flexibility. Unfortunately, the K receptor seems to be coupled to the sigma (a) receptor, which is implicated in psychotomimetic and dysphoric side effects. 

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