Modulation describes inhibitory and facilitatory effects of spinal interneurons on noxious transmission. In other words, modulation can be described as manipulating a noxious stimulus so it is perceived as a pain-suppressive transmission. This occurs at higher levels of the brainstem and midbrain. It is accomplished by an electrical or pharmacological stimulation of certain regions of the midbrain producing relief of pain. Not all analgesics are exogenous. Since opioid receptors in the brain are unlikely to exist for the purpose of responding to the administration of opium and its derivatives, then it must be endogenous compounds for which these receptors had evolved. Endogenous analgesics, including enkephalin (ENK), norepinephrine (NE), and gamma-aminobutyric acid (GABA) activate opioid, alpha-adrenergic, and other receptors that either inhibit release of glutamate from primary nociceptors or diminish post-synaptic responses of second-order neurons.

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