poppy”)—have been used since ancient Chinese and classical Greek times to modify
pain perception, but also misused for their euphoric effect. The opium alkaloids, called
opiates and including morphine, are centrally acting major analgesics(pain relievers)
that have a strong narcotic action, producing sedation and even loss of consciousness.
In contrast, the over-the-counter pain relievers like aspirin or acetaminophen are non-
narcotic and are better called minor analgesics.
At the time of the discovery of opiate receptors in 1973, it was assumed that only opi-
ates of plant origin existed. Thus, the presence, in animals, of very specific receptors for
a substance of plant origin was puzzling. Furthermore, these receptors were also found
in organs and brain regions not implicated in pain perception. The answer to these prob-
lems started to emerge in 1975, with the discovery of the endogenous opioid peptides,
the natural analgesics of animal organisms whose receptors, fortuitously, also bind
opiate alkaloids. There are several types of such peptides: the large endorphins (endoge-
nous morphins)isolated from the pituitary; and the small peptides, most importantly the
pentapeptideenkephalins[kephalos(Gr.) = “head”]. It eventually became evident that
the opioid peptides are neurohormones that are involved not only in pain perception, but
in a number of other physiological activities as well. On the basis of their many neuro-
nal effects, opioid peptides could also be considered peptide neurotransmitters. That
idea, however, might be an oversimplification; hence this topic has been considered in
this chapter, which deals with hormones.
5.18.1 Endogenous Opioid Peptide HormonesIn 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 electroanalgesiacould 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 neurotrans-
mitter with opiate-like properties.
The isolation of such endogenous opiates was reported simultaneously by four labo-
ratories: 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 purifi-
cation, two pentapeptides, called enkephalins, with the structures NH 2 -Tyr-Gly-Gly-
Phe-Met-COOH (5.83, Met-enkephalin) and NH 2 -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
HORMONES AND THEIR RECEPTORS 351