Evidence Showing That -Endorphin Regulates Cyclic Guanosine 3',5'-Monophosphate (cGMP) Efflux: Anatomical and Functional Support for an Interaction between Opiates and Nitric Oxide

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Abstract
Nitric oxide (NO) is now recognized as a diffusible messenger molecule that normally augments intercellular communication in the central nervous system, but is neurotoxic if released in excessive amounts. NO is synthesized from L-arginine by the Ca21/calmodulin- dependent neuronal isoform NO synthase (NOS) localized in sub- populations of neurons throughout the brain, including the hypothal- amus. In the hypothalamus, NO stimulates the release of GnRH, the primary neurohormone governing reproduction in mammals. Al- though the excitatory amino acid, glutamate, acting through the N- methyl-D-aspartate (NMDA) receptor is believed to be responsible for stimulation of NO release, the neuronal system(s) that inhibits NO efflux is unknown. As the endogenous opioids, primarily b-endorphin (bEND), exert a tonic restraint on GnRH secretion, we sought evi- dence for a possible functional link between bEND and NOS path- ways in the hypothalamus. We observed that restraining the opioid influence with the opiate receptor antagonist, naloxone, in intact, but not in castrated, rats rapidly augmented extracellular cGMP/NO ef- flux in the medial preoptic area, where GnRH, NOS, and bEND immunoreactive pathways are coextensive. Pituitary LH secretion increased in conjunction with this augmented cGMP/NO response and pretreatment with the m opiate receptor agonist, morphine, sup- pressed these naloxone-induced responses. Further, visualization of hypothalamic sections immunostained for both bEND and NOS re- vealed bEND-immunoreactive axon terminals in close proximity to NOS-positive cell bodies and dendrites in a number of hypothalamic subdivisions, including the medial preoptic area. These close appo- sitions represented conventional synapses between bEND nerve ter- minals and NOS-positive perikarya and dendrites under the electron microscope. Clearly, the experimental data, corroborated by morpho- logical evidence, point to a direct inhibitory control of bEND on NOS- immunoreactive neurons in monitoring cGMP/NO release. These findings together with the previous observations that the glutamate neurotransmitter acting through NMDA receptors located on NOS- immunopositive cells stimulates cGMP/NO efflux and plasma LH selectively in intact rats document the existence of a dual control comprised of the excitatory NMDA and the inhibitory m opiate re- ceptors in modulating cGMP/NO release, a response also directed by gonadal steroids. This new knowledge of an inhibitory opioid influ- ence on cGMP/NO release is probably extremely important both in the generation of periodicities in GnRH secretion that underlie hypotha- lamic control of reproduction and in protecting against neurotoxic overstimulation of NO release by excitatory amino acids. (Endocri- nology 138: 1537-1543, 1997)

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