Stress and IL-1beta contribute to the development of depressive-like behavior following peripheral nerve injury

Abstract

The physiological link between neuropathic pain and depression remains unknown despite a high comorbidity between these two disorders. A mouse model of spared nerve injury (SNI) was used to test the hypothesis that nerve injury precipitates depression through the induction of inflammation in the brain, and that prior exposure to stress exacerbates the behavioral and neuroinflammatory consequences of nerve injury. As compared with sham surgery, SNI induced mechanical allodynia, and significantly increased depressive-like behavior. Moreover, SNI animals displayed increased interleukin-1beta (IL-1beta) gene expression within the frontal cortex and concurrent increases in the expression of glial fibrillary acidic protein (GFAP) within the periaqueductal grey (PAG). Additionally, exposure to chronic restraint stress for 2 weeks before SNI exacerbated mechanical allodynia and depressive-like behavior, and resulted in an increase in IL-1beta gene expression in the frontal cortex and brain-derived neurotrophic factor (BDNF) gene expression in PAG. Treatment with metyrapone (MET), a corticosteroid synthesis inhibitor, before stress eliminated deleterious effects of chronic stress on SNI. Finally, this study showed that interference with IL-1beta signaling, through administration of IL-1 receptor antagonist (IL-1ra), ameliorated the effects of neuropathic pain on depressive-like behavior. Taken together, these data suggest that peripheral nerve injury leads to increased cytokine expression in the brain, which in turn, contributes to the development of depressive-like behavior. Furthermore, stress can facilitate the development of depressive-like behavior after nerve injury by promoting IL-1beta expression.

Figure 1

Assessment of allodynia and depressive-like behaviors. (a) SNI significantly decreases paw withdrawal threshold as compared with sham-operated animals on postsurgical days 3 and 7. Exposure to 14 consecutive days of chronic stress exacerbates SNI effects on threshold on post-SNI days 3 and 7. Chronic stress does not alter threshold in Sham animals. (b) SNI significantly increases the percentage time spent floating during a 5 min forced swim test conducted on day 7 after surgery. Exposure to 14 consecutive days of chronic stress exacerbates SNI effects on the forced swim test. Similar letters above error bars indicate no significant difference between groups (P > 0.05), whereas different letters represent a significant difference between groups (P < 0.05). Data are presented as mean ± s.e.m.

Figure 2

SNI influences on supraspinal gene expression and CORT levels on day 7. SNI significantly increases mRNA expression of GFAP (a) and BDNF (b) within the PAG and IL-1β (c) within the PFC. Chronic stress does not influence the expression of GFAP within the PAG (a). Chronic stress increased the expression of PAG BDNF (b) and IL-1β (c) among SNI animals. No chronic stress effects are detected in Sham-operated animals. (d) SNI alone does not alter CORT concentration at 7 days after surgery. Exposure to 14 days of chronic stress before surgery lead to significant increases in CORT levels within Sham and SNI animals, with SNI-chronic stress animals having the highest levels of CORT. Similar letters above error bars indicate no significant difference between groups (P > 0.05), whereas different letters represent a significant difference between groups (P < 0.05). Data are presented as mean ± s.e.m.

Figure 3

(a) Modification of stress effects on SNI-induced allodynia and depressive-like behavior by metyrapone. SNI significantly decreases threshold in all groups. Vehicle (VEH)-treated animals exposed to chronic stress before SNI surgery have significantly lower paw withdrawal thresholds. Inhibition of stress-induced CORT elevation through treatment with metyrapone (MET; 100 mg kg⁻¹) before restraint eliminates the effect of stress on SNI outcome. Data are presented as mean ± s.e.m. (b) Vehicle-treated chronic stress mice spend more time floating in the FST at day 7. Inhibition of stress-induced CORT elevation through treatment with metyrapone (MET, 100 mg kg⁻¹) eliminates the deleterious effect of chronic stress on SNI-induced depressive-like behavior. Similar letters above error bars indicate no significant difference between groups (P > 0.05), whereas different letters represent a significant difference between groups (P < 0.05). Data are presented as mean ± s.e.m.

Figure 4

Modification of stress effects on SNI-induced gene expression and depressive-like behavior by metyrapone. Neither chronic stress nor MET treatment influences (a) PAG GFAP mRNA expression. Inhibition of stress-induced CORT elevation through treatment with metyrapone (MET, 100 mg kg⁻¹), eliminates the effects of chronic stress on (b) PAG BNDF and (c) PFC IL-1β and mRNA expression. Inhibition of CORT synthesis during chronic stress eliminates the effects of pre-SNI stress on CORT levels measured a week after the final restrain session (d). Similar letters above error bars indicate no significant difference between groups (P > 0.05), whereas different letters represent a significant difference between groups (P < 0.05). Data are presented as mean ± s.e.m.

Figure 5

Influence of IL-1ra on SNI-induced depressive-like behavior. Percentage time spent floating during a 5-min forced swim test conducted on day 7 after surgery was used as an index of depressive-like behavior. The mice were fitted with a cannula targeting the left lateral ventricle 1 week before SNI or Sham surgery. IL-1ra (1.8 µg) or the vehicle (VEH; 2 µl aCSF) was administered on postoperative days 6 and 7. SNI animals treated with CSF spent more time floating in FST than the other three experimental groups. Administration of IL-1ra eliminated the effect of SNI on time spent floating, such that behavior in this group was not significantly different than either Sham group. Similar letters above error bars indicate no significant difference between groups (P > 0.05), whereas different letters represent a significant difference between groups (P < 0.05). Data are presented as mean ± s.e.m.