Table 2. Differentially expressed genes following E2 treatment.
List of known pain genes that were differentially expressed following steady-state treatment with diestrus-level E2 (Di), proestrus level E2 (Pro), supraphysiological-level E2 (Sp) E2, or vehicle (Veh) in ovariectomized female rats.
| Gene symbol |
Gene Name | Function | Comparison | Ref |
|---|---|---|---|---|
| Dao | Diamine oxidase | Scavenging extracellular histamine after mediator release | Pro > Veh Di > Veh |
[99] |
| Bdkrb2 | Bradykinin 2 receptor | Proinflammatory; pronociceptive | Pro > Veh Sp > Veh |
[95] |
| Cacna1g | Calcium channel subunit alpha 1G | Voltage-gated T-type calcium channel (Cav3.1) | Sp > Veh Pro > Veh |
[16] |
| Cacna1h | Calcium channel subunit alpha 1H | Voltage-gated T-type calcium channel (Cav3.2) | Sp > Veh Sp > Di |
[16] |
| Prrt2 | Prolein rich transmembrane protein | Negative regulator of Nav1.2/1.6 Complex disorders with migraine; type 4 familial hemiplegic migraine; in PRF pain genes |
Sp > Veh Sp > Di |
[35; 59] |
| Grin3a | NMDA receptor subunit 3a | Ionotropic glutamate receptor; involved in pain inhibition | Di > Veh Pro > Veh |
[81] |
| Gabrd | GABA receptor delta | Target for analgesia | Di > Sp | [70] |
| Adcyap1r1 | Pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1) | Involved in migraine Regulated by stress and E2 |
Pro > Veh Di > Veh Di > Sp |
[56; 128] |
| Adcyap1 | Pituitary adenylate cyclase-activating polypeptide 1 (PACAP) | Involved in migraine Neuropathic pain onset |
Pro < Veh Sp < Veh |
[29; 128] |
| Vip | Vasoactive intestinal polypeptide | Same superfamily as PACAP (glucagon/secretin); neuropathic pain maintenance | Pro < Veh Sp < Veh Sp < Di |
[29] |
| Prl | prolactin | Female-specific hyperalgesia Modulated by E2 |
Sp > Veh | [87; 115] |
| Calca | Calcitonin gene-related peptide alpha | Involved in migraine; female-specific responses in dura mater; prolactin increases release in female dura | Di < Veh Sp < Veh |
[5; 6; 128] |
| Calcb | Calcitonin gene-related peptide beta | Involved in migraine | Di < Veh Sp < Veh |
[128] |
| Fkbp5 | FK506 binding proteins | Co-chaperone of Hsp90 of steroid receptor complex (stabilizing and shuttling) Linked to stress disorders |
Pro > Veh Di > Veh |
[112; 125] |
| Atp1a2 | Na+/K+ pump subunit alpha 2 | Involved in familial migraine; E2 rescues age-related drop in ATPase; in PRF pain genes | Pro > Veh Di > Veh Sp > Veh |
[57; 59] |
| Timp3 | Metalloproteinase inhibitor 3 | Protects against cartilage degradation | Pro > Veh Di > Veh |
[61] |
| Cnr1 | Cannabinoid receptor 1 | Peripheral cannabinoid receptor; peripheral analgesia | Pro > Veh Di > Veh |
[123] |
| Faah | Fatty acid amide hydrolase | Inhibition reduces pain, linked to migraine; reduced FAAH leads to increased cannabinoid and 5HT activity; mutation leads to pain insensitivity; in PRF pain genes | Di < Veh Di > Sp |
[39; 82] |
| Rgs4 | Regulator of G protein signaling (RGS) 4 | Regulatory molecule that acts as a GTPase activating protein (GAP). Can deactivate Gi and Gq. Maintain chronic pain. | Pro < Veh Di > Sp |
[8] |
| S1pr3 | Sphingosine-1-phosphate receptor 3 | Acute mechanonociception via KCNQ2/3 (Pro > Veh) | Pro < Veh Sp < Veh |
[43] |
| Cttn | Cortactin | Actin rearrangement, regulates vascular permeability, works with S1P | Pro < Veh Sp < Veh |
[36] |
| Ptgds | Prostaglandin D2 synthase (PGD2) | Proinflammatory, produced by neuron, glia, immune cells Sex-dependent nociceptive signaling |
Di > Veh Sp > Veh |
[47; 111] |
| Insr | Insulin receptor | Insulin deficiency contributes to diabetic neuropathy | Pro > Veh Sp > Veh |
[127] |
| Lama4 | Laminin subunit alpha-4 | Heat pain sensitivity | Pro < Veh Sp < Veh |
[119] |
| Tmem165 | Transmembrane protein 165 | Intracellular calcium transporter | Pro < Veh Di < Veh |
[16] |
| Camk2a | Calcium/calmodulin dependent protein kinase II alpha | Serine/threonine protein kinase; loss contributes to switch from mechanoreception to pain | Di > Veh Sp > Veh |
[124] |
| Cd4 | CD4 molecule | Membrane glycoprotein of immune cells (T cells, B cells, macrophages) | Di < Veh Sp < Veh |
[74] |
| Bahcc1 | BAH domain and coiled-coil containing 1 | Unknown relevance to nociception, but was reported as a SNP in only females with TMD | Sp > Veh Sp > Di |
[98] |
| Fabp7 | Fatty acid binding protein 7 | Increased in DRG with nerve injury; related to regeneration and PPAR signaling | Sp < Veh Sp < Di |
[7; 27] |
| Col9a1 | Collagen type IX alpha chain | Mutation leads to painful stiff joints | Sp < Veh Sp < Di |
[19] |
| Disc1 | Disrupted in Schizophrenia (DISC1) scaffold protein | Deletion reduces thermal pain sensitivity | Di > Sp | [114] |
| Anxa1 | Annexin A1 | Anti-inflammatory; antinociceptive | Di > Sp | [90] |
| Clock | Circadian regulator | Dimerizes with bmal; target to reduce OA pain | Di > Sp | [26] |
| Nav2 | Neuron navigator, unc-53 homolog | Mutants have impaired sensory function; diminished TG and DRG sensory neurons | Di > Sp | [76] |
| P2rx3 | Purinergic receptor P2X3 | Orofacial pain (TMD) and burning mouth syndrome E2 reduces spinal P2X3 E2 attenuates P2X3 in DRG |
Sp > Di | [11; 69; 94; 102] |
| Cckbr | Cholecystokinin B receptor | Anti-opioid activity by heterodimerizing with MOR; E2 increases in MCF-7 cells | Sp > Di | [103] |
| Htr3A | 5HT3A receptor | Ionotropic, pain | Sp > Di | [31] |
| Per1 | Period circadian clock 1 | Altered in chronic migraine in male mice; alters chemokine release and mechanical hypersensitivity | Sp > Veh | [49; 83; 100] |
| Ptprz1 | protein tyrosine phosphatase receptor type Z1 | Alters responses to thermal and tactile stimuli | Di > Sp | [58] |