Sex Differences in Peripheral Mu-Opioid Receptor Mediated Analgesia in Rat Orofacial Persistent Pain Model

Abstract

Unilateral ligation of the tendon of anterior superficial part of rat masseter muscle (TASM) leads to long-lasting allodynia. Sex differences in peripheral mu-opioid receptor (MOR)-mediated analgesia under persistent myogenic pain are not well understood. In this study, we examined (1) whether locally applied MOR agonists attenuate persistent pain following TASM ligation in a sex dependent manner, (2) whether there are sex differences of MOR expression changes in rat trigeminal ganglia (TG). The effects of MOR agonist, D-Ala2, N–Me-Phe4, Gly5-ol]-Enkephalin acetate salt (DAMGO), were assessed 14 days after TASM ligation in male, female and orchidectomized (GDX) male rats. MOR mRNA and protein levels in TG 14 days following tendon ligation were also determined. The mechanical thresholds of the injured side were significantly decreased in both male and female rats, from 3 days to 28 days after TASM ligation. A10 μg DAMGO significantly attenuated allodynia in male rats. A 10-fold higher dose of DAMGO was required in female and GDX male rats to produce the level of anti- allodynia achieved in male rats. The level of MOR mRNA in TG from male rats was significantly greater 14 days after TASM ligation compared with the sham-operated male rats, but not from female and GDX male rats. After TASM ligation, males had significantly more MOR immunoreactivity in TG compared to sham-operated males. The MOR levels increased to 181.8% of the sham level in male rats receiving tendon injury. But there was no significant change in female rats receiving tendon injury compared to the sham female rats. Taken together, our data suggest that there were sex differences in the effects of peripheral MOR agonists between male and female rats under TASM ligation developing long-lasting pain condition, which is partly mediated by sex differences in the changes of MOR expressions and testosterone is an important factor in the regulation of MOR.

Impact of sex on pain and opioid analgesia: a review

“…Indeed, using a variety of acute and chronic pain assays, researchers have shown that morphine’s median effective dose in female rodents is approximately twice the concentration of the dose needed for males to achieve comparable levels of pain relief (Kepler et al, 1989; Cicero et al, 2002; Ji et al, 2006; Loyd and Murphy, 2006; Loyd et al, 2008; Posillico et al, 2015). Researchers using other opioids have reported similar results (Barrett et al, 2002; Bai et al, 2015). Studies investigating the side-effects of opioids suggest that in rodents, females suffer from higher rates of opioid-induced hyperalgesia than males (Holtman and Wala, 2005; Juni et al, 2008).…”

Androgen receptor transcriptionally regulates μ-opioid receptor expression in rat trigeminal ganglia

“…Since the level of AR receptor expression in TG is comparable between male and female rats (Lee et al, 2013), and that AR is hereby shown to bind to the Oprm1 promoter region in female TG, it is reasonable to assume that the circulating testosterone level in female is not sufficient to elicit MOR induction under inflammatory conditions. Such testosterone dependent regulation of MOR within TG has been demonstrated in a myositis model (Zhang et al, 2014) as well as in a tendon ligation model (Bai et al, 2015). In both models, inflammation- or injury-induced upregulation of MOR in TG is impaired in female and GDX rats and that testosterone replacement in GDX male rats restores the expression of MOR and the efficacy of peripherally administered MOR agonists.…”

The role of P2X3 receptors in bilateral masseter muscle allodynia in rats

“…We defined mechanical allodynia as the presence of a nocifensive behavioral response evoked at a mechanical threshold that previously did not evoke a nocifensive response. Changes in nocifensive behavioral responses were evaluated by using previously described methods (3,23,24). To confirm bilateral allodynia, the nocifensive behavior response after unilateral CFA or saline injection into the masseter muscle was measured bilaterally at different time points using a von Frey anesthesiometer (VFA; type 2391, IITC Inc., Woodland Hills, CA, USA) with the tip size of 1.0 mm.…”