Catechol-O-methyltransferase polymorphism Val158Met is associated with distal neuropathic pain in HIV-associated sensory neuropathy.

BACKGROUND: Many of those aging with HIV suffer from distal neuropathic pain (DNP) due to HIV-associated sensory neuropathy (HIV-SN). Prior studies have linked chronic pain conditions to a variant of the catechol-O-methyltransferase (COMT), ValMet. This variant confers reduced enzymatic activity and results in higher synaptic dopamine levels. Here we examined the role of ValMet as a predictor of DNP in HIV-SN. METHODS: In 1044 HIV-infected individuals enrolled in CNS HIV Antiretroviral Therapy Effects Research, an observational study across six US institutions, we characterized the relationship between ValMet and DNP in HIV-SN. Participants underwent neurologic examination and genotyping. Stratification into genetic ancestry groups was employed to eliminate bias due to genetic background. FINDINGS: Of 590 participants with HIV-SN, 38% endorsed DNP, 24% reported nonpainful symptoms of neuropathy (paresthesia and numbness), and 38% were asymptomatic. Compared with asymptomatic HIV-SN, ValMet was associated with 2.3 higher odds of DNP. There were no increased odds of nonpainful symptoms. The association remained significant after controlling for other risk factors for DNP: lifetime diagnosis of depression, older age, ancestry, cumulative exposure to dideoxynucleoside antiretrovirals, diabetes, and nadir CD4. Stratified by genetic ancestry, the association between ValMet and DNP was significant in European and African genetic ancestry. INTERPRETATION: ValMet may be a genetic marker for susceptibility to DNP in HIV-SN. Our findings support the notion that differences in pain processing mediated by COMT-related dopamine signaling play a role in susceptibility to DNP in HIV-SN. Because prior studies suggest that the COMT allele may influence dose-response relationships with opioid treatment, knowing COMT genotype could influence management.

Publisher Correction: A craniofacial-specific monosynaptic circuit enables heightened affective pain.

In the version of this article initially published, ORCID links were missing for authors Erica Rodriguez, Koji Toda and Fan Wang. The error has been corrected in the HTML and PDF versions of the article.

A craniofacial-specific monosynaptic circuit enables heightened affective pain.

Humans often rank craniofacial pain as more severe than body pain. Evidence suggests that a stimulus of the same intensity induces stronger pain in the face than in the body. However, the underlying neural circuitry for the differential processing of facial versus bodily pain remains unknown. Interestingly, the lateral parabrachial nucleus (PBL), a critical node in the affective pain circuit, is activated more strongly by noxious stimulation of the face than of the hindpaw. Using a novel activity-dependent technology called CANE developed in our laboratory, we identified and selectively labeled noxious-stimulus-activated PBL neurons and performed comprehensive anatomical input-output mapping. Surprisingly, we uncovered a hitherto uncharacterized monosynaptic connection between cranial sensory neurons and the PBL-nociceptive neurons. Optogenetic activation of this monosynaptic craniofacial-to-PBL projection induced robust escape and avoidance behaviors and stress calls, whereas optogenetic silencing specifically reduced facial nociception. The monosynaptic circuit revealed here provides a neural substrate for heightened craniofacial affective pain.