Progesterone Application to the Rat Forehead Produces Corneal Antinociception

Abstract

PurposeOcular pain and discomfort are the most defining symptoms of dry eye disease. We determined the ability of topical progesterone to affect corneal sensitivity and brainstem processing of nociceptive inputs.MethodsProgesterone or vehicle gel was applied to the shaved forehead in male Sprague Dawley rats. As a site control, gel also was applied to the cheek on the side contralateral to corneal stimulation. Corneal mechanical thresholds were determined using the Cochet-Bonnet esthesiometer in intact and lacrimal gland excision–induced dry eye animals. Eye wipe behaviors in response to hypertonic saline and capsaicin were examined, and corneal mustard oil-induced c-Fos immunohistochemistry was quantified in the brainstem spinal trigeminal nucleus.ResultsProgesterone gel application to the forehead, but not the contralateral cheek, increased corneal mechanical thresholds in intact and lacrimal gland excision animals beginning <30 minutes after treatment. Subcutaneous injection of the local anesthetic bupivacaine into the forehead region before application of progesterone prevented the increase in corneal mechanical thresholds. Furthermore, progesterone decreased capsaicin-evoked eye wipe behavior in intact animals and hypertonic saline evoked eye wipe behavior in dry eye animals. The number of Fos-positive neurons located in the caudal region of the spinal trigeminal nucleus after corneal mustard oil application was reduced in progesterone-treated animals.ConclusionsResults from this study indicate that progesterone, when applied to the forehead, produces analgesia as indicated by increased corneal mechanical thresholds and decreased nociceptive responses to hypertonic saline and capsaicin.

How does ocular graft‐versus‐host disease fit under the dry eye umbrella? A review

“…1% progesterone gel administered on the forehead was found to reduce the frequency and severity of symptoms in individuals with coGVHD after 6 weeks compared to placebo (SANDE; scale: 0–100) (progesterone: mean reduction: −26.3, standard error [SE]: 4.1 vs. placebo: −5.6, SE: 5.8) as well as signs after 2 weeks compared to placebo (CFS) (progesterone: mean reduction: −2.5, SE: 0.5 vs. placebo: −0.2, SE: 0.8, p < 0.05) 128 . In rats with intact or excised lacrimal glands, 1% progesterone was found to provide corneal antinociception 129 . More data are needed on the impact of hormones as a treatment for GVHD.…”

“…128 In rats with intact or excised lacrimal glands, 1% progesterone was found to provide corneal antinociception. 129 More data are needed on the impact of hormones as a treatment for GVHD.…”

Sigma-1 receptors and progesterone metabolizing enzymes in nociceptive sensory neurons of the female rat trigeminal ganglia: A neural substrate for the antinociceptive actions of progesterone

“…Although estrogen has been reported to be both pronociceptive and antinociceptive in various pain models, 22,[25][26][27][28][29] the research literature exclusively reports that progesterone is anti-inflammatory and antinociceptive . [30][31][32][33][34][35][36] We have recently reported that estrogen increases pain behaviors in a rat model of inflammatory TMD pain which is reversed with progesterone treatment. 37 Progesterone is also metabolized by 5α-reductase to 5α-dihydroprogesterone, which is then converted to the metabolite allopregnanolone by 3α-hydroxysteroid dehydrogenase (3α-HSD), thus progesterone's protective effects can occur through its metabolite allopregnanolone.…”