Endogenous pain modulation: Magnitude and direction of effect of corticotropin-releasing factor (CRF) on inflammatory pain in rats depend on sex and pain measure

Abstract

Corticotropin-releasing factor (CRF) can act at all levels of the neuraxis to produce analgesia (Lariviere and Melzack, 2000), and may have a significant role in prolonged clinical pain. The current study examined whether central CRF could contribute to observed sex differences in inflammatory pain or the modulation thereof. Male and female Wistar rats (n=6-9) received intracerebroventricular (ICV) injections of CRF (700 ng), alpha helical-CRF (ahCRF, 10 ug), or saline (5 ul), 5 min prior to the formalin inflammatory pain test. Rats received a hind paw intraplantar injection of 10% formalin (50 ul, for comparison with previous studies). Pain behaviors (licking, lifting/elevating, and shaking the injected paw) and non-pain behaviors (exploration time, rearing, sitting alert, crouching, and grooming) were recorded for 60 min after formalin injection. ICV CRF injection produced significant analgesia (p<0.05) in the interphase depression of the formalin pain response (10-15 min post-injection), seen as a decrease in the time spent elevating the injected paw, and replicating our previous findings (unpublished). This analgesia was greater in males than in females. In contrast, hyperalgesia was observed in both the first phase (5 min) and the second phase (30-60 min) of the formalin response as an increase in the time spent licking the injected paw without any effect on other individual pain responses and without sex differences. ahCRF did not have a significant effect on formalin pain responding. The sex differences in the analgesic response to ICV CRF may be due to similar sex differences observed by others in the effect of ICV CRF on locus coeruleus neuron activity. The unexpected hyperalgesia observed, but not observed with 2.5% formalin used previously by us, may indicate specificity of effects on neural substrates underlying individual pain behaviors or may indicate an important role of stimulus intensity in the functional activity of CRF.