Sex-related differences in descending norepinephrine and serotonin controls of spinal withdrawal reflex during intramuscular saline induced muscle nociception in rats.

Sex-associated differences in the perception and modulation of pain have widely been reported in humans as well as animals. The aim of the present study performed in conscious rats of both sexes was to systematically investigate the role of sex in endogenous descending controls of nociceptive paw withdrawal reflex during experimental muscle pain elicited by intramuscular (i.m.) injection with different doses (0.1-0.4 ml of 0.9-5.8%) of saline. Ipsilateral i.m. injection of 0.2-0.4 ml, but not 0.1 ml, isotonic (0.9%, IT) saline elicited long lasting (about 7d), secondary and contralateral mechanical hyperalgesia in female rats, whereas male rats exhibited a bilateral, short-term (less than 1d) mechanical hyperalgesia only during the exposure to 0.4 ml IT saline injection (P < 0.05). A bolus of 0.4 ml, but not 0.1-0.2 ml, IT saline significantly induced a one-week, secondary and contralateral heat hypoalgesia in both male and female rats (P < 0.05). In contrast to the IT saline injection, 0.1 ml hypertonic (5.8%, HT) saline started to evoke bilateral mechanical hyperalgesia in male and female rats. During the HT saline induced muscle nociception, mechanical hyperalgesia in female rats was greater in magnitude and longer in duration than that of in male rats (P < 0.05). Heat hypoalgesia was bilaterally found in male rats receiving either 0.2 ml or 0.4 ml HT saline injection, whereas female rats showed heat hypoalgesia, subjected only to the 0.4 ml HT saline injection (P < 0.05 and P < 0.001). Intrathecal (i.th.) administration of either 6-hydroxydopamine hydrobromide (6-OHDA) or 5,7-dihydroxytryptamine (5,7-DHT) significantly attenuated the HT saline induced heat hypoalgesia, not mechanical hyperalgesia, in male rats. By contrast, in female rats i.th. 6-OHDA markedly blocked heat hypoalgesia, and mechanical hyperalgesia was prevented by 5,7-DHT treatment. It is suggested that i.m. injection of saline dose-dependently elicits ipsilateral secondary and contralateral mechanical hyperalgesia and heat hypoalgesia, which are differently modulated by descending noradrenaline (NA) and serotonin (5-HT) pathways in rats of both sexes. Importantly, the present findings here are not only consistent with our previous study indicating a supraspinal nociception discriminator with different triggering thresholds to govern peripheral A-δ and C-fiber mediated responses (You et al., 2010), but further strengthen this hypothesis that compared with male rats, supraspinal nociception discriminator in female rats exhibits a lower facilitatory threshold and a higher inhibitory threshold. This may bring our attention to better understand why females are commonly reported to be more sensitive and less tolerant to noxious stimulation. In conclusion, sex-related differences are important in descending modulations of pain and anesthesia. Less noxious stimuli could activate descending inhibition in males but not females, whereas less noxious afferents may elicit descending facilitation in female, but not male rats. Central noradrenergic and serotonergic pathways are differently involved in the action of descending modulations of nociception in rats of both sexes.