Figure 4. Chronic intrathecal morphine and methadone administration produce significant tolerance, hyperalgesia, allodynia, and alterations in mRNA and/or protein levels of cytokines, chemokines and a glial activation marker.

Animals were administered once daily 15 µg morphine (A,B), 15 µg methadone (C,D) or saline (in 1 µl with a 25 µl flush) intrathecally for 7 days via an indwelling catheter. On days 1 (black square and triangle), 4 (black square and triangle with dark gray center) and 7 (black square and triangle with light gray center) animals were tested for short baseline latency Hargreaves stimuli (A,C) to assess analgesia and long baseline latency Hargreaves stimuli (B,D) to assess hyperalgesia over a 2 hr timecourse following drug administration. Significant reductions in analgesia were observed across the multiple days dosing, indicating the development of tolerance (A,C) and hyperalgesia (B,D). Mechanical allodynia (E) was assessed using von Frey filaments 60 min prior and 2 hr after administration on day 1 and day 4 and only 60 min prior to drug administration on day 7 for morphine (black square), methadone (black triangle) or saline (black circle with white center). *** P < 0.001