Analgesic effects of dietary caloric restriction in adult mice

Nociception was studied in male mice, mostly of the C57BL/6 strain, during continuous or prolonged restriction of caloric intake (60% of ad-libitum) from midlife to senescence (up to 105 weeks). Restricted mice showed fewer licking or biting responses 20-60 min after hind paw injection of 5% formalin at 46 and 70 weeks, but not at 93 weeks. Also, they showed longer response latencies around 46 weeks of age in the 52°C hot-plate test, which partial tail amputation failed to affect, although it did produce at least 2 weeks of chronic neuropathic hypersensitivity in ad libitum controls. Injection of collagen subcutaneously at 36-42 weeks led to chronic hyperalgesia in the DBA/1 but not the C57BL/6 strain, measured weekly by the barely nociceptive 50°C hot-plate test to minimize damage. This collagen-induced arthritic hyperalgesia was then gradually and reversibly blocked during 9-15 weeks of caloric restriction starting at 53-58 weeks. In longitudinal trials on normal mice, performed every 2-4 weeks between 42 and 105 weeks with the 50°C hot-plate, caloric restriction led to altered latencies (higher relative to controls) only in the last 10-20 weeks, perhaps because it delayed the onset of age-related peripheral neuropathies. In conclusion, long-term caloric restriction leads to significant hypoalgesia in pre-senescent mice subjected to above-threshold pain of widely different durations, the effect disappearing at later ages unless spontaneous neuropathies become influential. A reduction in cumulative food intake thus appears to generate antinociceptive signals in adult male mice, perhaps serving specifically to promote riskier behavior during prolonged food shortages.