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.