Systemic administration of analgesics can lead to serious adverse side effects compromising therapeutic benefit in some patients. Information coding pain transmits along an afferent neuronal network, the first synapses of which reside principally in the spinal cord. Delivery of compounds to spinal cord, the intended site of action for some analgesics, is potentially a more efficient and precise method for inhibiting the pain signal. Activation of specific proteins that reside in spinal neuronal membranes can result in hyperpolarization of secondary neurons, which can prevent transmission of the pain signal. This is one of the mechanisms by which opioids induce analgesia. The spinal cord is enriched in such molecular targets, the activation of which inhibit the transmission of the pain signal early in the afferent neuronal network. This review describes the pre-clinical models that enable new target discovery and development of novel analgesics for site-directed pain management.