Pain in infancy is a distinct clinical concern and is managed sub-optimally. The study of pain processing during early life has shown that in mammals, nocifensive withdrawal thresholds are lower, and response magnitudes are greater and longer lastingcompared to adults.The central nervous system is highly plastic during postnatal development, and maturation of nociception requires activity-dependent processes to attain an adult-like state (see Hathway, 2014). Normal adult processing of noxious sensory inputs requires a constant balance between synaptic excitation and inhibition within the “Pain Pathway”. Descending neuromodulatory pathways play a key role in modulating spinally mediated nociceptive reflexes. The periaqueductal grey (PAG) and nuclei within the rostroventral medial medulla (RVM) are pivotal within this loop for the top-down control of spinal dorsal horn (DH) pain processing (see Hathway, 2014). Both the PAG and RVM integrate pain-related activity from forebrain structures and bi-directionally modulate DH excitability. Opioidergic activity within the descending pathway is one of the major neurotransmitter systems responsible for endogenous pain control. Our work and others have previously shown that significant postnatal refinement occur in the opioidergic signalling system (Hathway et al., 2009, 2012; Kwok et al., 2014). This immaturity of CNS processing of pain does not just reflect the altered properties of efferent structures from the mid-brain and brainstem but also extends to structures such as the primary somatosensory cortex which receive ascending input from the DH via the thalamus (Devonshire, Greenspon and Hathway 2015). In this talk I will discuss altered pain processing within CNS structures during postnatal development and present evidence that shows that early life pain experience alters the normal development of these structures. I will also present new data that maps the functional maturation of the endocannabinoid systems within the PAG, RVM and DH from a molecular to whole animal physiological level. All animal use procedures were performed in accordance with the UK Home Office Animals (Scientific Procedures) Act 1986 and followed the guidelines of the International Association for the Study of Pain. Using Sprague-Dawley rats of both genders electromyographic (EMG) recording from biceps femoris of the hind limb, hind limb reflex withdrawal magnitude, threshold and duration were recorded in response to innocuous and noxious mechanical stimuli in light-anaesthetised rats of increasing postnatal age (postnatal (P) day 10, 21 and 40 (adult); see Kwok et al., 2014). In the PAG microinjection of synthetic cannabinoids (HU210, 4μg, CB1/CB2 receptor agonist; AM251, 2.77μg, CB1 receptor antagonist) significantly decreased reflex excitability, an effect also seen when these drugs were applied to the RVM. The paradoxical ability of both agonist and antagonist to mediate the same effect in the same tissue was resolved when it was considered that AM251 is also a weak agonist at the GPR55 receptor. Intra-PAG or RVM microinjection of the GPR55 receptor agonist LPI (lysophosphoinositol) (12μg) significantly reduced spinal excitability at P10 and P21 but had no effect when administered in adult PAG and increased reflex excitability when administered to adult RVM. Tissue levels of the eCBs (anandamide (AEA), 2-acylglycerol (2-AG), oleoylethanolamide (OEA) and palmitoylethanolamide (PEA) were assessed. Significant age-related alterations in the levels of all eCBs were detected in all three structures studied. These changes in lipid levels were also accompanied by alterations in transcript levels of components of the eCB system. Within the PAG levels of NAPE-PLD (a synthetic enzyme for AEA), significantly increased with age, whilst levels of the CB1 receptor decreased. Within the DH levels of mRNA for this enzyme were elevated at P21 compared to both P10 and adult. In the RVM GPR55 mRNA levels were significantly elevated at P21 compared to both P10 and adults. Immunohistochemical analysis identified clear alterations in the expression pattern and immunofluorescent intensity of CB1, CB2, NAPE-PLD and DAGLα throughout the PAG, RVM, DH axis. As well as alterations in opioidergic systems in the postnatal period there are concurrent changes in eCB pathways that play a role in the normal maturation of pain detection and responding. The impact of alterations in top-down pain processing in early life and the effect of early life injury to alter these processes has considerable implications for life-long health and well-being.