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

Abstract

Temporomandibular joint disorder (TMD) is associated with pain in the joint (temporomandibular joint, TMJ) and muscles involved in mastication. TMD pain dissipates following menopause but returns in some women undergoing estrogen replacement therapy. Progesterone has both anti-inflammatory and antinociceptive properties, while estrogen's effects on nociception are variable and highly dependent on both natural hormone fluctuations and estrogen dosage during pharmacological treatments, with high doses increasing pain. Allopregnanolone, a progesterone metabolite and positive allosteric modulator of the GABA A receptor, also has antinociceptive properties. While progesterone and allopregnanolone are antinociceptive, their effect on estrogen-exacerbated TMD pain has not been determined. We hypothesized that removing the source of endogenous ovarian hormones would reduce inflammatory allodynia in the TMJ of rats and both progesterone and allopregnanolone would attenuate the estrogen-provoked return of allodynia. Baseline mechanical sensitivity was measured in female Sprague-Dawley rats (150-175 g) using the von Frey filament method followed by a unilateral injection of complete Freund's adjuvant (CFA) into the TMJ. Mechanical allodynia was confirmed 24 h later; then rats were ovariectomized or received sham surgery. Two weeks later, allodynia was reassessed and rats received one of the following subcutaneous hormone treatments over 5 days: a daily pharmacological dose of estradiol benzoate (E2; 50 µg/kg), daily E2 and pharmacological to sub-physiological doses of progesterone (P4; 16 mg/kg, 16 µg/kg, or 16 ng/kg), E2 daily and interrupted P4 given every other day, daily P4, or daily vehicle control. A separate group of animals received allopregnanolone (0.16 mg/kg) instead of P4. Allodynia was reassessed 1 h following injections. Here, we report that CFA-evoked mechanical allodynia was attenuated following ovariectomy and daily high E2 treatment triggered the return of allodynia, which was rapidly attenuated when P4 was also administered either daily or every other day. Allopregnanolone treatment, whether daily or every other day, also attenuated estrogen-exacerbated

Preclinical models of deep craniofacial nociception and temporomandibular disorder pain

“…Evidence has demonstrated the sex differences in the deep craniofacial nociception [ 37 , [80] , [81] , [82] ]. The underlying mechanisms of sex differences in TMD pain have been investigated in the preclinical studies from the point of changes in the level of sex hormones, and several hormones such as estrogen [ [83] , [84] , [85] ], progesterone [ 86 , 87 ] and testosterone [ 88 ] play roles. In this article, we will not discuss this issue, which is described elsewhere [ [89] , [90] , [91] ].…”

“…Local inflammatory model is developed by the injection of chemical substance into the deep craniofacial tissues. For example, chemicals including CFA (complete Freund’s adjuvant) [ 16 , 86 , 102 , 103 ], formalin [ [104] , [105] , [106] , [107] ], mustard oil [ 108 , 109 ], carrageenan [ 105 , 110 , 111 ], serotonin (5HT) [ 112 , 113 ], ATP [ 114 , 115 ], capsaicin [ 116 , 117 ], monosodium iodoacetate [ 80 , 118 ] and zymosan [ 105 , 119 ] have been used. In this article, we focus on two preclinical models produced by the local administration of CFA or formalin to discuss, because these models have been often employed to study the basis for TMD pain.…”

Prevalência de sintomas de disfunção temporomandibular, fatores associados e impacto sobre a qualidade de vida em usuários da rede de atenção primária à saúde

“…Acredita-se que a maior prevalência de DTM em mulheres deve-se a maior preocupação destas com a saúde, refletindo em maior procura por serviços relacionados à DTM e Dor Orofacial (Moura et al, 2017;Paulino et al, 2018). Por outro lado, estudos realizados em modelos animais de inflamação têm demonstrado que a redução dos níveis de estrógeno resultou em redução da inflamação da articulação temporomandibular (Guan et al, 2005)e do comportamento nociceptivo (Hornung et al, 2020), sugerindo que o estrógeno pode estar associado à fisiopatologia desta disfunção (List & Jensen, 2017).…”

“…Sua etiologia é multifatorial, destacando-se diversos fatores que podem agir como predisponentes, perpetuantes ou desencadeantes (Chisnoiu et al, 2015;De Leeuw & Klasser, 2013;Okeson, 2013). Entre estes fatores, podem ser mencionados: traumas e hipermobilidade articular (De Leeuw & Klasser, 2013;Ögren et al, 2012); hábitos parafuncionais, incluindo bruxismo noturno e diurno (Paulino et al, 2018;Wagner & Filho, 2018); fatores oclusais (Bilgiç & Gelgör, 2017;Lemos, Moreira, et al, 2015); desordens do sono, como apnéia e ronco (Benoliel et al, 2017;Wagner & Filho, 2018); fatores psicológicos, incluindo estresse, ansiedade e depressão (Fillingim et al, 2013;Yap & Natu, 2020); diferenças hormonais (Guan et al, 2005;Hornung et al, 2020) e fatores genéticos, como o polimorfismos no transportador de serotonina (5HTT) e catecol-O-metiltransferase (COMT) (Brancher et al, 2019).…”

Acute and Preventive Management of Migraine during Menstruation and Menopause

“…Notably, both estrogens [ 15 ] and oxytocin [ 16 ] might act on the trigeminal ganglion and modulate the release of calcitonin gene-related peptide (CGRP), which is implied in the generation of migraine pain. Progestins might also attenuate pain responses via conversion to the neurosteroid allopregnanolone, as suggested by animal evidence [ 17 ]. Taken all together, female sex hormones influence the susceptibility to migraine, acting through a complex interplay of central and peripheral pathways ( Figure 1 ).…”