This Week in The Journal

D5 Dopamine Receptors Contribute to Pain Only in Males

Salim Megat, Stephanie Shiers, Jamie K. Moy, Paulino Barragan-Iglesias, Grishma Pradhan, et al.

Tissue injury and inflammation can trigger changes in pain circuitry that cause subsequent insults to produce abnormally prolonged pain. This so-called hyperalgesic priming is thought to contribute to some chronic pain conditions, including headache, low-back pain, and repetitive stress injuries. In experimental animals, hyperalgesic priming is induced by injecting an irritant or inflammatory agent such as carrageenan, interleukin-6, or brain-derived neurotrophic factor (BDNF) into a paw. These agents produce acute hypersensitivity to thermal and mechanical stimuli that resolves in ∼4 d. Hyperalgesic priming is then revealed by injecting prostaglandin E2 (PGE2). Whereas this normally causes brief (∼1 h) mechanical hypersensitivity, hypersensitivity persists for >24 in primed animals.

One contributor to hyperalgesic priming is signaling through D1-like dopamine receptors (D1LRs) in the spinal cord. D1LRs include D1- and D5-type receptors, both of which are expressed in nociceptors and spinal circuits. To determine which of these receptors is involved in hyperalgesic priming, Megat et al. used D5 knock-out mice. Injection of interleukin-6 produced similar amounts of mechanical hypersensitivity in control and D5-deficient male mice, but the priming revealed by subsequent PGE2 injection was attenuated in mutants. Hyperalgesic priming induced by BDNF and carrageenan were also reduced in D5-deficient male mice, as were acute hypersensitivity produced by these agents and baseline behavioral responses to noxious chemical and thermal stimuli. Surprisingly, however, pain responses and hyperalgesic priming in D5-deficient female mice were similar to those in controls. Moreover, priming was attenuated by a D1LR antagonist in D5-deficient females, but not in males. Additional experiments revealed that D5-receptor mRNA levels were higher in the dorsal horn and dorsal root ganglion of male than of female mice.

These results suggest that hyperalgesic priming is sexually dimorphic, relying on D5 dopamine receptors in males and D1 receptors in females. D5 receptors also contribute more to basal thermal and chemical sensitivity in males than in females. The difference in sensitivity likely stems from the higher expression of D5 receptors in nociceptive circuits in males. These results underscore yet again that pain processing involves different cellular and molecular mechanisms in male and female rodents, emphasizing the need to explore such differences in humans and develop sex-specific therapies where needed.

UBE3A Regulates Caspase-Dependent Dendritic Pruning

Natasha Khatri, James P. Gilbert, Yuda Huo, Roozhin Sharaflari, Michael Nee, et al.

(see pages 363–378)

Caspase-3 is best known as a driver of apoptosis, but localized, sublethal activation of caspase-3 contributes to many essential cellular processes, including neural stem-cell differentiation, axonal pathfinding and branching, dendritic pruning, and synaptic plasticity. Dysregulation of caspase activity might therefore contribute to neurodevelopmental and neurodegenerative disorders not only by inducing apoptosis, but also by disrupting neuronal growth and plasticity (Unsain and Barker 2015 Neuron 88:461). Indeed, Khatri et al. provide evidence that hyperactivation of caspase-3 contributes to neuronal pathology in some forms of autism.

Dendrites of Layer 5 pyramidal cells were shorter in mice possessing multiple maternal copies of UBE3A (left) than in controls (right). See Khatri et al. for details.

Multiple maternal copies of a chromosomal fragment containing UBE3A are present in 1–2% of people with autism, and mutant mice possessing three copies of UBE3A exhibit behaviors reminiscent of those in autism, including reductions in social interaction and vocal communication. Khatri et al. found that although the lamination pattern and the number and distribution of neurons in the cortex were normal in mice possessing multiple copies of UBE3A, the overall length of the dendritic arbor, the number of dendritic branches, and dendritic spine density were lower in neurons from mutant mice than in wild-type. Similarly, overexpressing E6AP, the protein encoded by UBE3A, in cultured hippocampal neurons caused loss of dendritic branches and spines. After E6AP expression was induced, existing dendrites became thinner or fragmented, and ultimately were removed. This was preceded by loss of microtubules in distal dendrites.

E6AP is a ubiquitin ligase: by attaching ubiquitin to other proteins, it targets them for degradation. Khatri et al. found that E6AP overexpression increased ubiquitination and degradation of XIAP, a protein that normally inhibits activated caspase-3. Consequently, caspase-3 activation was elevated in hippocampal neurons overexpressing E6AP. This, in turn, increased cleavage of tubulin. Importantly, overexpressing XIAP, inhibiting caspase-3 activity, overexpressing tubulin, or stabilizing microtubules prevented dendritic retraction in E6AP-overexpressing neurons.

These results suggest that by targeting XIAP for degradation, E6AP enables activated caspase-3 to cleave targets, including tubulin. This function may be necessary for normal dendritic or synaptic pruning in cortex and hippocampus; but in individuals with multiple copies of UBE3A, excess production of E6AP leads to excessive degradation of XIAP and consequently, hyperactivation of caspase-3 and excessive dendritic pruning. This might contribute to autism symptoms.