Oestrogen receptor-immunoreactive neurons in the trigeminal sensory system of male and cycling female rats
Introduction
Considerable experimental and clinical evidence suggests that sex-related factors contribute to various aspects of pain processing.1, 2, 3, 4 Many common pain conditions mediated by the trigeminal nerve [e.g. migraine headache, temporomandibular joint (TMJ) disorders, dry eye disease, burning mouth syndrome] are more prevalent in women than men.4, 5, 6, 7, 8 The basis for sex differences in craniofacial pain is not known; however, one possible factor is the action of oestrogen on trigeminal neurons. Oestrogen acts by binding to specific receptors in the plasma membrane and cytoplasm to modulate neural activity through alterations in gene transcription, ion channel activity and intracellular cascades.9, 10, 11, 12 The classical oestrogen receptor exists as alpha (ERα) and beta (ERβ) isoforms. In the rodent spinal cord, ERα is dominant and localised mainly in the superficial laminae.13, 14, 15 In the trigeminal brainstem complex (TBC), ERα-positive neurons are most numerous in the superficial laminae of the trigeminal subnucleus caudalis (Vc) of female rats16, 17, 18, 19 with weaker staining for ERβ14; however, it is not known if males and females display similar levels of expression. The Vc shares several anatomical features with the spinal dorsal horn and plays a critical role in trigeminal pain processing.20, 21, 22, 23 C-fos immunocytochemistry24 and electrophysiological25 results have shown that the activity of TMJ-responsive neurons in the superficial laminae of the Vc varied over the oestrous cycle in the rat consistent with a link to sex hormone status. It is well established that dorsal root ganglion (DRG) cells at spinal levels contain ER protein26, 27, 28, 29; however, it is not known to what extent trigeminal ganglion (Vg) neurons also contain ER protein. The aim of the present study was to quantify the number of ERα-positive neurons in the TBC and Vg in male and cycling female rats to determine if changes in the number of labelled neurons could account for the sex differences observed by others in experimental models of craniofacial pain.
Section snippets
Materials and methods
The experimental protocols were approved by the Institutional Animal Care and Use Committee of Rhode Island Hospital and conformed to the established guidelines set by The National Institute of Health guide for the care and use of laboratory animals (Publication No. 99-158, revised 2002).
Distribution of ER in the lower brainstem and upper cervical spinal cord
Cells containing ERα-immunoreactivity were found in discrete regions of the lower brainstem and upper cervical spinal cord (Fig. 1). At the level of the obex (Fig. 1A), several labelled cells were seen at the Vi/Vc transition region (see example in Fig. 2A). Numerous labelled cells were also found in the caudal-lateral portions of the nucleus tractus solitarii (NTS) and the ventrolateral medulla. Only scattered ERα-positive cells were seen within the TBC, NTS or ventrolateral medulla rostral to
Discussion
The main findings of this study revealed a high density of ERα-positive neurons in laminae I–III of the Vc and the upper cervical spinal cord, and the number of labelled cells was significantly greater in prooestrous or dioestrous females than males. Few ERα-labelled cells were seen in the deep laminae of the Vc or rostral portions of the TBC regardless of sex hormone status. The number of ERα-positive cells in laminae I–III of the Vc in females did not vary over the oestrous cycle. However, in
Acknowledgement
This study was supported in part by a grant from the National Institute of Dental and Craniofacial Research (DE 12758).
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