Table 2.
Sex differences and hormonal modulation of deep somatic stimuli a
| Ref | Species/prep | Test (stim→response) | Result | Additional results and Notes |
|---|---|---|---|---|
| Sex difference | ||||
| (Burnes et al., 2008) | Mouse/ M,F,OVx, +testosterone | Muscle fatigue; ASIC3 wildtype and KO | Wt: F>M=OVx+T. KO: Fwt=MKO>Mwt. | Greater muscle fatigue (pain) in females. Testosterone was protective against muscle pain (low pH) but dependent on ASIC3. |
| Niu (Niu et al., 2012) | Rat/ M,F | masseter CFA→ mechanosensitivity | M=F. CB1R agonist: antihyperalgsia M>F | No SD in muscle hyperalgesia, but SD in peripheral modulation of muscle pain by CB1R agonist. Speculate testosterone is antinociceptive/protective. |
| Cairns (Cairns et al., 2002) | Rat/ M,F,OVx,GDx, +E2 | Glu, m.oil in TMJ → jaw muscle activity | F>M (Glu); OVx↓,+E2↑; GDx,+E2 no change. m.oil: ↑activity but no SD. | Glutamate sensitized TMJ to further inflammation w/o SD. E2 in OVx was pronociceptive to glutamate. |
| Gaumond (Gaumond et al., 2002) | Rat/ M,F,GDx,OVx | Hindpaw formalin response | F>M: I, interphase, II; F>OVx: interphase; GDx>M: I, late II; OVx=GDx. | Formalin evoked greater responses in females, suggests E2 was antinociceptive by decreasing interphase inhibition; Testosterone was protective; GDx eliminated sex difference. |
| Coulombe (Coulombe et al., 2011) | Mice/ M,F, OVx+α/β agonist, ERαKO, ERβKO | Hindpaw formalin response | Interphase: ERβKO↓, β ag↑; Phase I: ERαKO↑, α ag↓. ↑ | In females, ERα was antinociceptive, ERβ was pronociceptive (↓ inhibitory mechanisms). Minimal effect in males. |
| Zhang (Zhang et al., 2012) | Rat/ M,F,OVx,+E2, antags | Hindpaw Mech Threshold, Thermal Threshold; Formalin response | E2 ↓MTh, ↓TTh: M=F=OVx. Formalin males: ↓ by ICI, G-15, ATD | Spinal E2 was pronociceptive in M and F (no SD); mERs mediated effects of E2. |
| Joseph (Joseph and Levine, 2003) | Rat/ M,F,OVx,+E2 | Chemotherapy-Induced Peripheral Neuropathy | F>M; OVx↓SD; E2 ↑SD; GDx: no effect. Inhibit PKCε: ↓hyp in M=OVx>>E2,F | CIPN F>M; SD was E2 dependent, E2 was pronociceptive. PKCε modulated pain but did not explain SD or E2 effect. |
| Spooner (Spooner et al., 2007) | Mice/ M,F, ERβKO | Hindpaw formalin response; Hot plate | Wt>KO; female effect only; Fos: wt>KO; HP:F=FβKO>M=MβKO | E2 was pronociceptive via ERβ dampening endogenous pain inhibitory mechanism→ ↑ spinal nociceptive activity. Females more sensitive to HP, ERβ independent. |
| Gaumond (Gaumond et al., 2005) | Rat/ M,F,GDx,OVx +E2, +T for 3wks | Hindpaw formalin response | GDx ↑phase I, II, T↓ I,II; OVx ↓ interphase; E+Prog restored interphase; E2, Prog had no effect. | GDx increased formalin response, reversed by testosterone (antinociceptive). OVx increased interphase inhibition, reversed by E2+prog (anti-inhibitory). |
| Pajot (Pajot et al., 2003) | Rat/ M,F,GDx,OVx | Formalin response to lip, foot | Lip: OVx>F; GDx=M. Foot: OVx=F, GDx=M. | E2 was antinociceptive to lip formalin, not hindpaw. Orofacial region more sensitive than hindpaw. |
| Ma (Ma et al., 2011) | Rat/ M,F,OVx,+E2, GDx | OVx induced Mech hyperalgesia, ATP antag in hindpaw | Mhyp: OVx>E2; GDx:no effect. ATPantag: reversed OVx Mhyp; GDx:no effect. | E2 was antinociceptive. E2 in females modulated P2X3 signal transduction, pain. Genomic mechanism. OVx↑, E2↓ P2X mRNA, protein in DRG. |
| Fischer (Fischer et al., 2008) | Rat/M,F,OVx,+E2, GDx | Glutamate/formalin in TMJ | di>p,M; OVx=di>F | E2 was antinociceptive to intra TMJ glutamate or formalin. No effect of estrous cycle phases during formalin test. |
| Hormone modulation | ||||
| Aloisi (Aloisi et al., 2003) | Rat/ M, GDx | Hindpaw formalin response, repeated injections | GDx increased formalin response over time | Testosterone was protective |
| Ceccarelli (Ceccarelli et al., 2006) | Rat/ F, OVx | Hindpaw formalin response, repeated injections | F>OVx | Cycling hormones were pronociceptive vs. OVx. Females had greater Fos expression in the arcuate nucleus. |
| Ceccarelli (Ceccarelli et al., 2003) | Rat/ F, longterm OVx (6 months) | Hindpaw formalin; thermal pain | Formalin licking: OVx>F; flinching, flexing OVx=F; | Replacement E2 antinociceptive to supraspinal (licking), but not spinal (flick, flex) responses to formalin. |
| Kuba (Kuba et al., 2005) | Rat/ OVx, +E2 | Hindpaw formalin response | OVx > E2 (phase II) E2 capsules ↓ late phase but only high concentration of formalin | E2 was antinociceptive. Chronic E2 from capsules potentially anti-inflammatory in periphery. |
| Mannino (Mannino et al., 2007) | Rat/ F cycling, OVx, +E2 capsules | Hindpaw formalin response | OVx> p=E2 | E2 was antinociceptive |
| Sanoja (Sanoja and Cervero, 2005; Sanoja and Cervero, 2008) | Mice/F,OVx,+E2 | Mech hyp; Therm hyp; colonic capsaicin | Mhyp: OVx>E2. Thyp: no effect. Cap behavior: OVx>E2. No effect of estrous cycle. | E2 was antinociceptive. OVx increased hyperalgesia which was reversed by E2. |
| Fischer (Fischer et al., 2007) | Rat/M,F,GDx,OVx,+T | TMJ formalin response | GDx>M; OVx=OVx+T; GDx=GDx+E2>GDx+T | Testosterone was protective decreasing the formalin response in males. E2 had no effect in GDx. Testosterone had no effect in GDx. |
a
Behavior: only those aspects of paper relevant to sex differences or hormonal modulation of behavioral responses are listed.
Abbreviations: M,F,p,e,met,di: intact male, intact female, proestrous, estrous, metestrous, diestrous; OVx: ovariectomized; +E2: OVx with E2 replacement; GDx: gonadectomy in males; +T: GDx + testosterone replacement; SD: sex difference; ↑/↓: increase/decrease. ag: agonist; antag: antagonist; Glu: glutamate; KO: knockout; mER: membrane bound estrogen receptor; Pn: pelvic nerve; PPT: ERα agonist; m.oil: mustard oil; wt: wildtype; ICI: ICI-182,780; G-15: GPER antagonist; ATD: aromatase inhibitor;