Molecular mechanisms of hormones implicated in migraine and the translational implication for transgender patients

Migraine is a primary headache disorder recognized by the World Health Organization as one of the most poorly understood and debilitating neurological conditions impacting global disability. Chronic pain disorders are more frequently diagnosed among cisgender women than men, suggesting that female sex hormones could be responsible for mediating chronic pain, including migraine and/or that androgens can be protective. This review discusses the major gonadal hormones, estrogens, progesterone, and testosterone in the context of molecular mechanisms by which they play a role in migraine pathophysiology. In addition, the literature to date describing roles of minor sex hormones including prolactin, luteinizing hormone, follicular stimulating hormone, and gonadotropin releasing hormone in migraine are presented. Because transgender and gender non-conforming (trans*) individuals are an underserved patient population in which gender-affirming sex hormone replacement therapy (HRT) is often medically necessary to align biological sex with gender identity, results from cisgender patient populations are discussed in the context of these major and minor sex hormones on migraine incidence and management in trans* patients

Cdk5-mediated CRMP2 phosphorylation is necessary and sufficient for peripheral neuropathic pain

Neuropathic pain results from nerve injuries that cause ectopic firing and increased nociceptive signal transmission due to activation of key membrane receptors and channels. The dysregulation of trafficking of voltage-gated ion channels is an emerging mechanism in the etiology of neuropathic pain. We identify increased phosphorylation of collapsin response mediator protein 2 (CRMP2), a protein reported to regulate presynaptic voltage-gated calcium and sodium channels. A spared nerve injury (SNI) increased expression of a cyclin dependent kinase 5 (Cdk5)-phosphorylated form of CRMP2 in the dorsal horn of the spinal cord and the dorsal root ganglia (DRG) in the ipsilateral (injured) versus the contralateral (non-injured) sites. Biochemical fractionation of spinal cord from SNI rats revealed the increase in Cdk5-mediated CRMP2 phosphorylation to be enriched to pre-synaptic sites. CRMP2 has emerged as a central node in assembling nociceptive signaling complexes. Knockdown of CRMP2 using a small interfering RNA (siRNA) reversed SNI-induced mechanical allodynia implicating CRMP2 expression as necessary for neuropathic pain. Intrathecal expression of a CRMP2 resistant to phosphorylation by Cdk5 normalized SNI-induced mechanical allodynia, whereas mimicking constitutive phosphorylation of CRMP2 resulted in induction of mechanical allodynia in naïve rats. Collectively, these results demonstrate that Cdk5-mediated CRMP2 phosphorylation is both necessary and sufficient for peripheral neuropathic pain. Keywords: Spared nerve injury, Neuropathic pain, CRMP2, Cyclin-dependent kinase 5, Phosphorylatio

Two phenotypic classes of second order solitary tract (ST) neurons have similar ST-evoked excitatory synaptic current (EPSC) responses but very different spontaneous EPSC rates between TRPV1+ and TRPV1- ST afferents.

<p>Shocks to the ST (arrowheads) evoked time-invariant glutamate release from TRPV1+ (A) and TRPV1- (B) types of neurons. Across neurons (C), evoked glutamate release was indistinguishable between afferent types (p = 0.2, t-test). Spontaneous EPSC rates (i.e. sEPSCs) in TRPV1+ neurons (D) were higher than TRPV1- neurons (E).Original traces are from the same neurons; A and D representing a single TRPV1+ neuron while B and D are from the same TRPV1- neuron. Across neurons (F), the rate of sEPSCs is much higher (p = 0.04, t-test) than from TRPV1- afferents. The results suggest that TRPV1+ afferents have a more active spontaneous glutamate release process than TRPV1-. Exposure to 100 nM capsaicin tested whether neurons were TRPV1+ or TRPV1- (not shown).</p

Increases in bath temperature progressively shortened the evoked ST-EPSC latency but event amplitudes were constant.

<p>In a single, representative TRPV1+ NTS neuron, latencies (black, A, B) were quite consistent over 5 representative trials of ST shocks with temperature held at a steady 31.9°C. B is expanded to show just the initial inward current of the ST-eEPSC. Note that the amplitudes (A, expanded in C) normally vary somewhat from trial to trial despite fixed conditions. (D-I) As temperature is increased, ST-eEPSCs arrive progressively earlier (unique colors for each temperature (E-F) and (H-I)). Note that event amplitudes are similarly variable, not ordered by temperature and have similar averages (p = 0.1, One way ANOVA). Traces were low-pass filtered for clarity (Gaussian). Dotted lines represent the indicated times (in ms) elapsed from the solitary tract shock across all 3 middle panels (B, E, H).</p

In TRPV1+ NTS neurons, temperature increased the rate of action potential firing.

<p>(A) In this current clamp recording trace, warming the bath temperature (red) near 37°C briskly increased the rate of action potentials. The shapes of the action potentials changed little from 32°C (blue) to 37°C (red) in expanded traces (B). Resting membrane potential ~ 57 mV at 32°C.</p

The rate of sEPSCs in TRPV1+ neurons closely track with temperature but not in TRPV1- neurons.

<p>We applied two ramps (0.1 V every 20 s) to generate changes in bath temperature (red) from 32° to 37°C and back to 32°C while sEPSCs were continuously recorded from second order NTS neurons. (A) In a representative TRPV1+ neuron, sEPSC frequency (10 s bins black/filled grey) tracked with bath temperature (10 s bins). (B) Across neurons, the average frequency of sEPSCs more than doubles with a 5°C increase in temperature (p < 0.01, Two Way RM ANOVA). (C) sEPSCs from this TRPV1- neuron do not track with temperature. (D) In a representative TRPV1- neuron, TRPV1 sEPSCs failed to track with temperature. (D) Across TRPV1- neurons, sEPSCs frequency was unchanged (p = 0.3, Two Way RM ANOVA).</p