The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females

Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naïve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting OIH through activation of PRLR-S in female mice. Deletion of both PRLR-L and PRLR-S (total PRLR) prevented, whereas PRLR-L overexpression rescued established OIH selectively in females. Inhibition of circulating PRL with cabergoline, a dopamine D2 agonist, up-regulated PRLR-L and prevented OIH only in females. The PRLR-L isoform therefore confers protection against PRL-promoted pain in females. Limiting PRL/PRLR-S signaling pharmacologically or with gene therapies targeting the PRLR may be effective for reducing pain in a female-selective manner.

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Faculty Opinions recommendation of The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737321616.793571434 ◽

2020 ◽

Author(s):

Irina Vetter

Keyword(s):

Prolactin Receptor ◽

Opioid Induced Hyperalgesia

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Microstructural analysis of the anorectic effect of N-0437, a highly selective dopamine D2 agonist

Brain Research ◽

10.1016/0006-8993(89)90603-3 ◽

1989 ◽

Vol 494 (2) ◽

pp. 350-358 ◽

Cited By ~ 28

Author(s):

Ilene N. Rusk ◽

Steven J. Cooper

Keyword(s):

Microstructural Analysis ◽

Dopamine D2 ◽

D2 Agonist ◽

Anorectic Effect ◽

Dopamine D2 Agonist ◽

Selective Dopamine

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Comparing axon regeneration in male and female mice after peripheral nerve injury

Journal of Neuroscience Research ◽

10.1002/jnr.24955 ◽

2021 ◽

Author(s):

Eun‐Hae Jang ◽

Yun‐Hee Bae ◽

Eun Mo Yang ◽

Yunho Gim ◽

Hyun‐Jun Suh ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Injury ◽

Peripheral Nerve Injury ◽

Axon Regeneration ◽

Male And Female ◽

Female Mice

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The effect of B-HT 920, a dopamine D2 agonist, on bar-press feeding in the monkey

Physiology & Behavior ◽

10.1016/0031-9384(94)90397-2 ◽

1994 ◽

Vol 55 (6) ◽

pp. 1125-1130 ◽

Cited By ~ 2

Author(s):

Shuji Aou ◽

Masaharu Mizuno ◽

Tetsuro Hori ◽

Katsushi Yamada

Keyword(s):

Dopamine D2 ◽

D2 Agonist ◽

Dopamine D2 Agonist

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Excitation by talipexole, a dopamine D2 agonist, of caudate nucleus neurons activated by nigral stimulation

Life Sciences ◽

10.1016/0024-3205(94)00497-8 ◽

1994 ◽

Vol 54 (14) ◽

pp. 957-966 ◽

Cited By ~ 8

Author(s):

Naoyuki Todo ◽

Toshihiko Momiyama ◽

Taku Amano ◽

Yasuko Kohno ◽

Masashi Sasa

Keyword(s):

Caudate Nucleus ◽

Dopamine D2 ◽

D2 Agonist ◽

Dopamine D2 Agonist

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Effects of Latanoprost and GLC756, a Novel Dopamine D2 Agonist and D1 Antagonist, on Cultured Normal Human Dermal Fibroblasts

European Journal of Ophthalmology ◽

10.1177/112067210601600112 ◽

2006 ◽

Vol 16 (1) ◽

pp. 67-72 ◽

Cited By ~ 3

Author(s):

U.W. Laengle ◽

R. Markstein ◽

D. Pralet ◽

B. Greiner ◽

D. Roman

Keyword(s):

Dermal Fibroblasts ◽

Human Dermal Fibroblasts ◽

Dopamine D2 ◽

D2 Agonist ◽

Normal Human ◽

Dopamine D2 Agonist ◽

Normal Human Dermal Fibroblasts

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Behavioral effects of cabergoline, a dopamine D2 agonist, on MPTP-induced parkinsonism in cynomolgus monkeys.

The Japanese Journal of Pharmacology ◽

10.1016/s0021-5198(19)50331-6 ◽

1994 ◽

Vol 64 ◽

pp. 172

Author(s):

Nobuhiko Arai ◽

Masayuki Isaji ◽

Hiroshi Miyata ◽

Eiji Mizuta ◽

Sadako Kuno

Keyword(s):

Behavioral Effects ◽

Cynomolgus Monkeys ◽

Dopamine D2 ◽

D2 Agonist ◽

Dopamine D2 Agonist

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Analgesic effects of optogenetic inhibition of basolateral amygdala inputs into the prefrontal cortex in nerve injured female mice

Molecular Brain ◽

10.1186/s13041-019-0529-1 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 2

Author(s):

Vinicius M. Gadotti ◽

Zizhen Zhang ◽

Junting Huang ◽

Gerald W. Zamponi

Keyword(s):

Prefrontal Cortex ◽

Nerve Injury ◽

Basolateral Amygdala ◽

Thermal Hyperalgesia ◽

Pyramidal Cells ◽

Male Mice ◽

Female Mice ◽

Analgesic Effects ◽

Induced Changes ◽

Thermal Stimuli

AbstractPeripheral nerve injury can lead to remodeling of brain circuits, and this can cause chronification of pain. We have recently reported that male mice subjected to spared injury of the sciatic nerve undergo changes in the function of the medial prefrontal cortex (mPFC) that culminate in reduced output of layer 5 pyramidal cells. More recently, we have shown that this is mediated by alterations in synaptic inputs from the basolateral amygdala (BLA) into GABAergic interneurons in the mPFC. Optogenetic inhibition of these inputs reversed mechanical allodynia and thermal hyperalgesia in male mice. It is known that the processing of pain signals can exhibit marked sex differences. We therefore tested whether the dysregulation of BLA to mPFC signaling is equally altered in female mice. Injection of AAV-Arch3.0 constructs into the BLA followed by implantation of a fiberoptic cannula into the mPFC in sham and SNI operated female mice was carried out, and pain behavioral responses were measured in response to yellow light mediated activation of this inhibitory opsin. Our data reveal that Arch3.0 activation leads to a marked increase in paw withdrawal thresholds and latencies in response to mechanical and thermal stimuli, respectively. However, we did not observe nerve injury-induced changes in mPFC layer 5 pyramidal cell output in female mice. Hence, the observed light-induced analgesic effects may be due to compensation for dysregulated neuronal circuits downstream of the mPFC.

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Conscious perception and the modulatory role of dopamine: no effect of the dopamine D2 agonist cabergoline on visual masking, the attentional blink, and probabilistic discrimination

Psychopharmacology ◽

10.1007/s00213-020-05579-9 ◽

2020 ◽

Vol 237 (9) ◽

pp. 2855-2872

Author(s):

E.A Boonstra ◽

M.R van Schouwenburg ◽

A.K Seth ◽

M Bauer ◽

J.B Zantvoord ◽

...

Keyword(s):

Attentional Blink ◽

Visual Masking ◽

Pharmacological Study ◽

Event Related Potential ◽

Striatal Dopamine ◽

Conscious Perception ◽

Double Blind ◽

Dopamine D2 ◽

D2 Agonist ◽

Dopamine D2 Agonist

Abstract Rationale Conscious perception is thought to depend on global amplification of sensory input. In recent years, striatal dopamine has been proposed to be involved in gating information and conscious access, due to its modulatory influence on thalamocortical connectivity. Objectives Since much of the evidence that implicates striatal dopamine is correlational, we conducted a double-blind crossover pharmacological study in which we administered cabergoline—a dopamine D2 agonist—and placebo to 30 healthy participants. Under both conditions, we subjected participants to several well-established experimental conscious-perception paradigms, such as backward masking and the attentional blink task. Results We found no evidence in support of an effect of cabergoline on conscious perception: key behavioral and event-related potential (ERP) findings associated with each of these tasks were unaffected by cabergoline. Conclusions Our results cast doubt on a causal role for dopamine in visual perception. It remains an open possibility that dopamine has causal effects in other tasks, perhaps where perceptual uncertainty is more prominent.

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