Patients　suffering　with　functional　somatic　pain　syndromes　such　as　temporomandibular　disorders　(TMD)　and　fibromyalgia　syndrome　(FMS)　have　some　similar　symptoms,　but　the　underlying　cause　is　still　unclear.　The　purpose　of　this　study　was　to　investigate　whether　5-HT2A　and　5-HT2C　receptors　in　the　spinal　cord　contribute　to　somatic　hyperalgesia　induced　by　orofacial　inflammation　combined　with　different　modes　of　stress.　Ovariectomized　rats　were　injected　subcutaneously　with　estradiol　and　bilateral　masseter　muscles　were　injected　with　complete　Freund＇s　adjuvant　followed　by　stress.　Somatic　sensitivity　was　assessed　with　thermal　and　mechanical　stimulation.　The　anxiety-　and　depression-like　behaviors　were　measured　by　immobility　time,　sucrose　preference,　elevated　plus　maze　and　open　field　tests.　The　expression　of　5-HT2A　and　5-HT2C　receptors　in　the　spinal　cord　was　examined　by　Western　blot.　Orofacial　inflammation　combined　with　11　day　forced　swim　stress　(FSS)　induced　persistent　mechanical　allodynia　for　15　days　and　thermal　hyperalgesia　for　2　days.　The　mechanical　and　thermal　hyperalgesia　lasted　for　43　days　and　30　days　respectively　following　orofacial　inflammation　combined　with　11　day　heterotypic　stress.　Orofacial　inflammation　combined　with　stress　induced　anxiety-　and　depression-like　behaviors.　The　expression　of　5-HT2A　and　5-HT2C　receptors　significantly　decreased　in　the　orofacial　inflammation　combined　with　stress　groups.　Intrathecal　injection　of　5-HT2A　or　5-HT2C　receptor　agonist　reversed　somatic　hyperalgesia.　The　results　suggest　that　down-regulation　of　5-HT2A　and　5-HT2C　receptors　in　the　spinal　cord　contributes　to　somatic　hyperalgesia　induced　by　orofacial　inflammation　combined　with　stress,　indicating　that　5-HT2A　and　5-HT2C　receptors　may　be　potential　targets　in　the　treatment　of　TMD　comorbid　with　FMS.　(C)　2020　IBRO.　Published　by　Elsevier　Ltd.　All　rights　reserved.