The Endogenous Neuromodulation System

This chapter focuses on the endogenous neuromodulation system. The concept of an endogenous pain control system has taken on different meanings as more details of the circuits and neurochemistry of pain regulatory networks have been elucidated. The brain stem exerts both facilitatory as well as inhibitory controls on the processing of nociceptive information at the level of the spinal cord. In fact, the nature of the postsynaptic effect of the monoamines depends directly on actions at specific receptor subtypes and on the intracellular machinery that is coupled to these receptors. Electrical stimulation applied to the midbrain PAG and other regions produces intense reversible analgesia in chronic pain patients. Such stimulation-induced analgesia is naloxone-reversible, emphasizing the role of an opioid sensitive pain modulatory circuit. An opioid-dependent descending pain inhibitory system has been demonstrated to mediate analgesia resulting from placebo. Studies have shown that the expectation of pain relief may activate pain inhibitory systems from the brain providing a basis for placebo-induced analgesia. The robust analgesic effects of opiate agonists such as morphine are likely to depend on mechanistic synergy resulting from opioid-induced activation of descending pain inhibitory projections from the medulla and inhibition of primary afferent input. The clinical relevance of descending inhibition is exemplified by the utility and maximal efficacy of morphine in treating severe pain, in spite of its receptor characteristics that suggest that this compound is a partial agonist.