Figure 5. Chronic intrathecal co-administration of anti-inflammatory treatments blunts the development of morphine tolerance, hyperalgesia and allodynia.
Animals received 20 µg morphine (in 1 µl with a 25 µl flush) twice daily via an indwelling intrathecal catheter, co-administered with IL-1ra (100 µg in 1 µl) plus Fc-IL-10 (250 ng in 5 µl; black triangle, point up), IL-1ra (100 µg in 1 µl) plus YVAD (500 ng in 5 µl; black triangle, point down), morphine co-administered with vehicles (black circle with gray center), or saline co-administered with vehicles (black square with white center). Fc-IL-10 is a stabilized human IL-10 which has an extended half-life. YVAD is a caspase-1 inhibitor, the enzyme that cleaves IL-1 into its mature form. YVAD will reduce the levels of mature active IL-1. The aim of Fc-IL-10 and YVAD treatments were to reduce the production of proinflammatory cytokines by producing an anti-inflammatory environment (Fc-IL-10) and by blocking the production of mature IL-1 (YVAD). IL-1ra was included to provide an immediate block of IL-1 actions. Animals were tested on days 1, 4 and 7 prior to, during and after the morning drug administration. The development of allodynia (von Frey; A), tolerance (short baseline latency Hargreaves stimuli; B) and hyperalgesia (long baseline latency Hargreaves stimuli; C) were measured. A two-way ANOVA with Bonferroni post hoc test was conducted to assess statistical significance between saline co-administered with vehicles versus the animals receiving morphine treatments (# P < 0.05, ##, P < 0.01 and ### P < 0.001), as well as the difference between morphine plus vehicles versus other treatments (* P < 0.05, ** P < 0.01 and *** P < 0.001).