Allopregnanolone suppresses mechanical allodynia and internalization of neurokinin-1 receptors at the spinal dorsal horn in a rat postoperative pain model

Abstract

BackgroundTo identify a new strategy for postoperative pain management, we investigated the analgesic effects of allopregnanolone (Allo) in an incisional pain model, and also assessed its effects on the activities of the primary afferent fibers at the dorsal horn.MethodsIn experiment 1, 45 rats were assigned to Control, Allo small-dose (0.16 mg/kg), and Allo large-dose (1.6 mg/kg) groups (n = 15 in each). The weight bearing and mechanical withdrawal thresholds of the hind limb were measured before and at 2, 24, 48, and 168 h after Brennan's surgery. In experiment 2, 16 rats were assigned to Control and Allo (0.16 mg/kg) groups (n = 8 in each). The degree of spontaneous pain was measured using the grimace scale after the surgery. Activities of the primary afferent fibers in the spinal cord (L6) were evaluated using immunohistochemical staining.ResultsIn experiment 1, the withdrawal threshold of the Allo small-dose group was significantly higher than that of the Control group at 2 h after surgery. Intergroup differences in weight bearing were not significant. In experiment 2, intergroup differences in the grimace scale scores were not significant. Substance P release in the Allo (0.16 mg/kg) group was significantly lower than that in the Control group.ConclusionsSystemic administration of Allo inhibited mechanical allodynia and activities of the primary afferent fibers at the dorsal horn in a rat postoperative pain model. Allo was proposed as a candidate for postoperative pain management.

Progesterone and Allopregnanolone Rapidly Attenuate Estrogen-Associated Mechanical Allodynia in Rats with Persistent Temporomandibular Joint Inflammation

“…In the present study, we observed a rapid attenuation in the reemergence of mechanical allodynia within 1 h of injection on day 1. This is in agreement with previous studies that investigated the effects of allopregnanolone in animal models of neuropathic pain (Charlet et al, 2008;Meyer et al, 2008Meyer et al, , 2011Ocvirk et al, 2008;Kawano et al, 2011;Svensson et al, 2013;Afrazi and Esmaeili-Mahani, 2014;Fujita et al, 2018). Surprisingly, allopregnanolone treatment did not attenuate the return of mechanical allodynia on day 3 or 5 of hormone treatment.…”

“…Allopregnanolone has been shown to have antinociceptive effects. Allopregnanolone attenuates diabetesinduced neuropathy (Afrazi and Esmaeili-Mahani, 2014), postoperative pain (Fujita et al, 2018), inflammatory pain (Charlet et al, 2008;Ocvirk et al, 2008), sciatic nerve ligation nociception (Meyer et al, 2008), and chemotherapyinduced nociception (Meyer et al, 2011). In the present study, we observed a rapid attenuation in the reemergence of mechanical allodynia within 1 h of injection on day 1.…”

“…The two lower doses (16 µg/kg or 16 ng/kg) of progesterone were chosen to include physiological to sub-physiological doses. The dose of allopregnanolone was chosen from a previous study reporting attenuation of mechanical allodynia in a rat model of post-operative neuropathic pain (Fujita et al, 2018).…”

<p>The Antiallodynic Effect of Nefopam on Vincristine-Induced Neuropathy in Mice</p>

“…35,39 Several studies have attempted to clarify the mechanism underlying the SP mediated responses and NK1 receptor internalization to investigate the feasibility of using NK1 receptor antagonist as a potential analgesics. 35,40,41 Our study demonstrated the analgesic effect of nefopam by validating NK1 receptor attenuation, which may reduce SP and NK1 signaling and lead to decreased nociceptive response.…”

Effect of Pregnenolone vs Placebo on Self-reported Chronic Low Back Pain Among US Military Veterans

“…Neurosteroids are endogenous molecules enriched in the brain that exhibit pleiotropic actions in the central nervous system. Allopregnanolone, a positive GABA A (γ-aminobutyric acid) receptor modulator 6,7 and downstream metabolite of pregnenolone, has known analgesic, [8][9][10][11][12][13][14] neuroprotective, [15][16][17][18][19][20][21] neurotrophic, 18 and anti-inflammatory properties. [22][23][24] Extensive data from preclinical models demonstrate that neurosteroids exhibit pronounced analgesic actions, and data demonstrate that neurosteroids are decreased in the setting of pain symptoms in clinical populations.…”