cholecystokinin and Peripheral-Nerve-Injuries

Individual differences in the effects of a chronic neuropathic injury on social behaviours characterize both the human experience and pre-clinical animal models. The impacts of these changes to the well-being of the individual are often underappreciated. Earlier work from our laboratory using GeneChip® microarrays identified increased cholecystokinin (CCK) gene expression in the periaqueductal gray (PAG) of rats that showed persistent changes in social interactions during a Resident-Intruder encounter following sciatic nerve chronic constriction injury (CCI). In this study, we confirmed these gene regulation patterns using RT-PCR and identified the anatomical location of the CCK-mRNA as well as the translated CCK peptides in the midbrains of rats with a CCI. We found that rats with persistent CCI-induced changes in social behaviours had increased CCK-mRNA in neurons of the ventrolateral PAG and dorsal raphe nuclei, as well as increased CCK-8 peptide expression in terminal boutons located in the lateral and ventrolateral PAG. The functional significance of these changes was explored by microinjecting small volumes of CCK-8 into the PAG of uninjured rats and observing their Resident-Intruder social interactions. Disturbances to social interactions identical to those observed in CCI rats were evoked when injection sites were located in the rostral lateral and ventrolateral PAG. We suggest that CCI-induced changes in CCK expression in these PAG regions contributes to the disruptions to social behaviours experienced by a subset of individuals with neuropathic injury.

Topics: Animals; Cholecystokinin; Escape Reaction; Male; Microinjections; Periaqueductal Gray; Peripheral Nerve Injuries; Rats; Rats, Sprague-Dawley; Sciatic Neuropathy; Sincalide; Social Interaction

Genetic invalidation of CCK(2) receptors abolishes chronic constriction injury (CCI) induced mechanical hypersensitivity in mice. However, housing in environmentally enriched conditions significantly alters the phenotype of CCK(2) receptor deficient mice in all major behavioral domains. Furthermore, environmental enrichment itself has been reported to have protective effects in several rodent models of neurological diseases (brain and spinal trauma, ischemic stroke, Alzheimer's disease, etc.). In the present study we reproduced the earlier finding that mice, lacking CCK(2) receptors (-/-) are resistant to CCI-induced hypersensitivity. On the other hand, environmental enrichment substantially reduced CCI-induced mechanical hypersensitivity in wild-type (+/+) mice. Nevertheless, the phenotypic differences between wild-type (+/+) and mutant (-/-) mice in mechanical sensitivity before and after CCI-surgery were not eliminated by alternative housing conditions. These observations suggest that environmental enrichment has beneficial effects in neuropathic conditions and reinforce the causal link between CCK(2) receptors, mechanical sensitivity and the development of CCI-induced hypersensitivity.

Topics: Animals; Cholecystokinin; Disease Models, Animal; Down-Regulation; Environment, Controlled; Female; Genetic Predisposition to Disease; Housing, Animal; Hyperalgesia; Ligation; Male; Mechanoreceptors; Mice; Mice, Inbred C57BL; Mice, Knockout; Peripheral Nerve Injuries; Peripheral Nerves; Peripheral Nervous System Diseases; Phenotype; Photic Stimulation; Receptor, Cholecystokinin B