Purine receptor antagonist modulates serology and affective behaviors in lupus-prone mice: evidence of autoimmune-induced pain?
Neurologic and psychiatric (NP) manifestations are severe complications of systemic lupus erythematosus (SLE). As commonly seen in patients, spontaneous disease onset in the MRL/MpJ-Fas(lpr)/J (MRL-lpr) mouse model of NP-SLE is accompanied by increased autoantibodies, pro-inflammatory cytokines and behavioral dysfunction which precede neuroinflammation and structural brain lesions. The role of purinergic receptors in the regulation of immunity and behavior remains largely unexplored in the field of neuropsychiatry. To examine the possibility that purinoception is involved in the development of affective behaviors, the P2X purinoceptor antagonist, suramin, was administered to lupus-prone mice from 5 to 14 weeks of age. In addition to food and water measures, novel object and sucrose preference tests were performed to assess neophobic anxiety- and anhedonic-like behaviors. Enzyme-linked immunosorbant assays for anti-nuclear antibodies (ANA) and pro-inflammatory cytokines were employed in immunopathological analyses. Changes in dendritic morphology in the hippocampal CA1 region were examined by a Golgi impregnation method. Suramin significantly lowered serum ANA and prevented behavioral deficits, but did not prevent neuronal atrophy in MRL-lpr animals. In a new batch of asymptomatic mice, systemic administration of corticosterone was found to induce aberrations in CA1 dendrites, comparable to the "stress" of chronic disease. The precise mechanism(s) through which purine receptor inhibition exerted beneficial effects is not known. The present data supports the hypothesis that activation of the peripheral immune system induces nociceptive-related behavioral symptomatology which is attenuated by the analgesic effects of suramin. Hypercortisolemia may also initiate neuronal damage, and metabolic perturbations may underlie neuro-immuno-endocrine imbalances in MRL-lpr mice.
Ballok
David A
DA
Department of Surgery (Neurosurgery, Neurobiology), McMaster University, Canada L8N 3Z5. ballokda@mcmaster.ca
Sakic
Boris
B
D000704:Analysis of Variance; D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000276:immunology; D001323:Autoantibodies / Q000378:metabolism; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D001835:Body Weight / Q000187:drug effects / Q000276:immunology; D048430:Cell Shape / Q000187:drug effects / Q000276:immunology; D003712:Dendrites / Q000276:immunology / Q000502:physiology; D004195:Disease Models, Animal; D004326:Drinking / Q000187:drug effects / Q000276:immunology; D004435:Eating / Q000187:drug effects / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005106:Exploratory Behavior / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D007249:Inflammation / Q000188:drug therapy*; D053583:Interleukin-1beta / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008822:Mice, Transgenic; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D009929:Organ Size / Q000187:drug effects / Q000276:immunology; D010146:Pain / Q000276:immunology*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000276:immunology; D013154:Spleen / Q000033:anatomy & histology / Q000276:immunology; D013498:Suramin / Q000008:administration & dosage* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000097:blood
D001323:Autoantibodies; D053583:Interleukin-1beta; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D014409:Tumor Necrosis Factor-alpha; D013498:Suramin