For this study, we used rodent models of chronic constriction injury of sciatic or trigeminal nerve to investigate the electrophysical responsiveness of single neurones to mechanical stimuli. This strategy allowed comparison of the degree of sensitisation in the two areas. We also examined changes in expression of NMDA receptor subunits and MAGUK proteins. Our results show a marked facilitation of responsiveness in thermal and mechanical behavioural reflexes in both spinal and trigeminal neuropathic pain models. Electrophysiological experiments indicated an increase in responsiveness of individual neurons to mechanical stimulation in spinal neuropathic animals but this increase was not as pronounced in trigeminal neuropathic animals. Further differences in electrophysiological response characteristics to various peripheral sensory stimuli between spinal and trigeminal neurons were shown in normal animals and following nerve injury. Biochemical experiments revealed that changes in expression of some NMDA receptor subunits, as well as associated MAGUK proteins, differed between spinal and trigeminal neuropathic animals, and within different regions of the trigeminal complex itself. We further investigated the potential role of proteins such as Persyn (known to influence cytoskeletal network integrity) and α-synuclein (implicated in cell death), which may particularly influence the development, duration or recovery from neuropathic pain. We investigated the role of persyn and α-synuclein proteins in neuropathic pain, using two null-expression mutant mouse strains. However, no significant differences were observed between phenotypes of these mutant animals and wild type animals following nerve injury. In conclusion, this study provides evidence for mechanistic differences in neuropathic sensitisation between trigeminal and spinal regions. These differences may lead to targets for improved therapeutic treatment of intractable pain states.