The streptozocin model of diabetes, induces neuropathic pain & changes in quality of life measures which can be modulated by social interaction/welfare

Many diabetic patients experience chronic neuropathic pain leading to reduced quality of life. More efficacious analgesics are needed as the majority of patients respond poorly. The predictive validity of animal models for analgesia may be improved by reinstating specific innate rodent wellbeing behaviours suppressed by pain (e.g. burrowing). In rats, systemic streptozocin (STZ) induces rapid & sustained changes that translate to diabetic patients i.e. hyperglycaemia, polydypsia & neuropathic pain. We investigated whether the development of STZ induced diabetes, in rats, reduces burrowing & sucrose preference (a measure of anhedonia) in line with neuropathic pain (static allodynia) & whether these wellbeing behaviours could be improved by the analgesic, pregabalin (PGB) &/or social paired housing. This work was conducted in accordance with guidelines established by the Animals (Scientific Procedures) Act 1986 / ASPA Amendment Regulations 2012. Male Wistar rats (325-425g) were administered a single i.p. injection of 65mgkg STZ or 20mM citrate buffer (pH4.5, CTRL). Animals; CTRL (N=16) or STZ (N=18) were pair housed into 5 CTRL/CTRL, 5 mixed STZ/CTRL & 6 STZ/STZ. 17 STZ rats developed hyperglycaemia (30.2  0.9 mmol/L, p<0.001) by day 7. Evoked static allodynia (Von Frey threshold) was evaluated using Dixon’s up-down method, burrowing behaviour in the home cage measured the amount of pea shingle (2.5kg) displaced from hollow plastic tubes (320 mm long x 100 mm diameter) & preference for 2% sucrose was expressed as a percentage of the total amount of liquid consumed each day. STZ pairs showed polydipsia & polyphagia as early as 2 & 7 days post injection. By day 3 post STZ diabetic animals possessed significant static allodynia (>70% had 68.2  4.2% change from baseline, p<0.001), impaired burrowing (680  172g, p<0.001) & reduced sucrose preference (20  13%, p<0.001) as compared with CTRL group (1650  149g; 84  2%). In STZ rats, impaired burrowing & anhedonia emerged at the same time as static allodynia. However, the anhedonia disappeared (64  4%, p>0.05) & the burrowing deteriorated further (102  38g, p<0.001) after 9 days, whilst the allodynia remained consistent over 18 days. PGB (30mgkg p.o. at 1 & 2 hours post treatment) completely reversed allodynia (PWT 1 hour, 19  2g, p<0.001) but not impaired burrowing (73.1  52g, p>0.05) as compared with VEH treated rats (PWT 3.1  0.3g, 86.7  78.9g) between day 14 & 18 post STZ. The early decline (day 3-10) in burrowing, in STZ rats, is significantly reversed if they burrow in pairs (day 3; 1571  159g, day 10; 848  159g, p<0.01) whilst pairing offers no social benefit to CTRL rats burrowing performance (p>0.05). PGB reversed the mechanical allodynia that developed following STZ injection, whereas the deficit in burrowing was left un-touched; suggesting different pathologies contribute to these two behaviours. Housing of CTRL rats with polydipsic STZ rats, in pain, alters their nociceptive responses & behaviour leading to hyperglycaemia, demonstrating rodents can recognize pain related responses in conspecifics. Social grouping of an STZ rat with a CTRL or STZ partner impacted on individual burrowing. If an STZ diabetic rat was paired with a CTRL rat it burrowed significantly more than an STZ diabetic rat that was paired with another STZ diabetic rat. Similarly, if a CTRL rat was paired with another CTRL rat it burrowed significantly more than a CTRL rat that was paired with an STZ diabetic rat. This alteration in burrowing, depending on home cage partner, suggests burrowing is measuring affective well-being of both CTRL & STZ diabetic rats & that social grouping of an STZ rat with a CTRL partner can have a positive impact on its welfare. We conclude that allodynia, anhedonia (as measured by the reduction in sucrose preference) & impaired burrowing in STZ diabetic rats may offer affective sensitive & objective quality of life measures of pain &/or diabetes. Furthermore it is clear that social pairing of diabetic rats can have a positive impact on welfare whilst the pairing of CTRL rats with diabetic rats in pain can have a negative impact.