Clinically, inflammatory pain is far more persistent than that typically modelled pre-clinically, with the majority of animal models focussing on short-term effects of the inflammatory pain response. The large attrition rate of compounds in the clinic which show pre-clinical efficacy suggests the need for novel models of, or approaches to, chronic inflammatory pain if novel mechanisms are to make it to the market. A model in which a more chronic inflammatory hypersensitivity phenotype is profiled may allow for a more clinically predictive tool. The aims of these studies were to characterise and validate a chronic model of inflammatory pain. We have shown that injection of a large volume of adjuvant to the intra-articular space of the rat knee results in a prolonged inflammatory pain response, compared to the response in an acute adjuvant model. Additionally, this model also results in a hypersensitive state in the presence and absence of inflammation. A range of clinically effective analgesics demonstrate activity in this chronic model, including morphine (3mg/kg, t.i.d.), dexamethasone (1mg/kg, b.i.d.), ibuprofen (30mg/kg, t.i.d.), etoricoxib (5mg/kg, b.i.d.) and rofecoxib (0.3-10mg/kg, b.i.d.). A further aim was to exemplify the utility of this chronic model over the more acute intra-plantar adjuvant model using two novel therapeutic approaches; NR2B selective NMDA receptor antagonism and iNOS inhibition. Our data shows that different effects were observed with these therapies when comparing the acute model with the model of chronic inflammatory joint pain. These data suggest that the chronic model may be more relevant to identifying mechanisms for the treatment of chronic inflammatory pain states in the clinic.

A clear interrelationship between biological rhythms and addiction has emerged from recent preclinical and clinical studies. In particular, the manipulation of the so-called 'clock genes' interferes with the manifestation of drug-related responses. For instance, Period 1 (Per1(Brdm1)) mutant mice do not display behavioural sensitization in response to repeated cocaine administration and do not express cocaine conditioned place preference, in contrast to control littermates. To assess the involvement of the mPer1 gene in a robust model of cocaine reinforcement and relapse-like behaviour, we tested Per1(Brdm1) mutant mice and their littermates for self-administration of several doses (0.06-0.75 mg/kg/infusion) of cocaine, and for reinstatement of an extinguished cocaine-seeking response. Per1(Brdm1) mutant mice did not differ from control littermates in their propensity to self-administer cocaine or to reinstate an extinguished cocaine-seeking behaviour in response to drug-associated cues or cocaine priming. In contrast to our earlier data on Per1(Brdm1) mutant mice in cocaine sensitization and conditioned place preference, this finding does not suggest a relationship between the circadian clock gene mPer1 in cocaine self-administration and reinstatement of cocaine-seeking behaviour. This study adds one further example to the notion that various behavioural tests usually used in addiction research rely on different neurobiological substrates.