Lack of tolerance development with long-term administration of PEGylated cholecystokinin

Cholecystokinin (CCK) is a short acting satiating peptide hormone produced in the proximal small intestine. Daily CCK injection in rats initially inhibits food intake, but after several days, food intake is no longer affected, suggesting development of tolerance. Previously, we covalently coupled CCK to a 10 kDa polyethylene glycol (mPEG-OH) and showed that this conjugate, PEG-CCK₉, produced a significantly longer anorectic effect than unmodified CCK₉. The present study examined whether tolerance to the anorectic effect develops during long-term administration of PEG-CCK₉. For 14 consecutive days, male Wistar rats (n = 12) received a daily i.p injection of 8 μg kg^-1 of PEG-CCK₉ and a control group received a daily control injection of mPEG-OH. Body weight and food intake were monitored daily during the experiment. Effects on the pancreas were investigated. On each day, injection of PEG-CCK₉ induced an anorectic effect lasting 3-6 h, but failed to significantly reduce daily total food intake compared to controls. The body weight gain of the PEG-CCK₉-treated animals was not different from controls. The PEG-CCK₉-treated group had a significantly higher pancreas weight, mainly due to hyperplasia. In conclusion, PEG-CCK₉ continued to have a daily suppressive effect on food intake when administered for 14 consecutive days, showing there was no development of tolerance.