Ontogeny of opiate mechanisms in relation to the sequential development of neurons known to be components of the guinea pig's enteric nervous system.

The development of opiate mechanisms in the guinea pig small intestine has been studied with reference to the development of transmitter mechanisms of neurons known to be components of the enteric nervous system. At 25 days' gestation neurons and a primitive neuropil could be found in the enteric mesenchyme. At this time, markers for two enteric neurotransmitters could be demonstrated; synthesis of [3H]acetylcholine ([3H]ACh) from [3H]choline, and specific axonal uptake of [3H]5-hydroxytryptamine ([3H]5-HT). This early gut also showed high affinity stereospecific binding of [3H]diprenorphine that was antagonized by levallorphan but not dextrophan. Thus, opiate receptors are detectable in the gut as soon as neurons can be identified. Neuronal precursors, however, are probably present prior to 25 days and putative serotonergic precursors were recognizable by their uptake of [3H]5-HT into cell bodies as early as day 20. Adrenergic innervation appeared gradually between days 32 and 48. Functional innervation of the longitudinal layer of smooth muscle was established much later in ontogeny. Spontaneous tone and a tetrodotoxin-sensitive 5-HT-induced relaxation of the muscle were detected at day 42 (neither norepinephrine nor ATP mediate this effect); contraction in response to ACh appeared at day 48; responses to electrical stimulation were elicited at days 50-56 and acute and chronic (tolerance-dependence) effects of opiates were apparent by day 56. The early appearance of opiate receptors is consistent with their being associated with either cholinergic or serotonergic neurons, or both. These early opiate receptors suggest that opiates or endogenous substances that act on opiate receptors might have effects not revealed by standard indices of opiate actions.