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The complexity of pain types and their associated pathways has frustrated attempts to rationally develop new classes of pain therapeutics. Figure 1 highlights some of this complexity, indicating a number of the targets known to be selectively expressed by nociceptive primary afferent nerves (eg.Na v1.8, TRPV1, ASICs, EP and α2-adrenergic receptors), presumed nociceptive dorsal horn neurons (eg. NK1 and NMDA receptor) and descending facilitatory and inhibitory modulatory pathways originating in the medulla, particularly the rostral ventromedial medulla. The functional expression of some targets on presumed nociceptive afferents (eg those that express markers such as TRPV1) is known, but knowledge of expression ofsubtypes (eg. VSCC splice variants) or accessory subunits that confer selectivity on some toxins) is very limited. We will use ion channel and receptor selective venom peptides  as they are identified and structurally optimised, to dissect the functional targets expressed by neurons in specific pain pathways classified by the expression of other markers and anatomical targets.  Figure 1 further illustrates the complexity of pain by identifying signalling system adaptations producing sensitisation in chronic pain states (eg. Nav1.8 redistribution) and changes in descending modulation (eg. 5-HT) that appear to mediate at least some aspects of ongoing pain  We will use chronic pain models established at PMRI to identify adaptations that change or modify target proteins and accessory subunits or co-factors in pain pathways, and examine target function directly in chronic pain models using venom peptides.