Hint1 gene deficiency enhances the supraspinal nociceptive sensitivity in mice

Abstract

IntroductionPrevious studies have indicated a possible role of histidine triad nucleotide‐binding protein 1 (HINT1) on sustaining the regulatory crosstalk of N‐methyl‐D‐aspartate acid glutamate receptors (NMDARs) and G‐protein‐coupled receptors (GPCRs) such as the μ‐opioid receptor (MOR). Both receptors are present in the midbrain periaqueductal gray neurons, an area that plays a central role in the supraspinal antinociceptive process.MethodsIn the present study, a battery of pain‐related behavioral experiments was applied to Hint1 knockout, heterozygous and wild‐type mice. Both the male and female mice were investigated to assess the differences between genders.Results Hint1−/− mice presented significant shorter latency at 50°C in both male and female in hot plate test while no significant difference was found in tail filck test. In Von Frey hairs test Hint1−/− mice were more sensitive than Hint1+/+ mice, presenting a lower withdrawal threshold and enhanced relative frequency of paw withdrawal. The average flinches and licking time of Hint1−/− mice were more than that of Hint1+/+ mice in formalin test.ConclusionThe absence of Hint1 gene‐enhanced supraspinal nociceptive sensitivity in mice, including thermal, mechanical and inflammatory hyperalgesia. Meanwhile, there was no certain evidence indicating the haploinsufficiency and gender differences of Hint1 gene in pain‐related behaviors.

HINT1 neuropathy in Norway: clinical, genetic and functional profiling

“…In patients with peripheral neuropathy, pain is a relatively frequent but underreported symptom [ 15 ]. Although the causal association between pain and HINT1 neuropathy is uncertain, studies in HINT1 KO mice showed a link with nociception and demonstrated a modulatory effect on the cannabinoid pathway [ 16 , 17 ]. Moreover, P1 had non-classical symptoms suggesting CNS involvement, ranging from late language development to social behavioral alterations.…”

Machine learning-based automated phenotyping of inflammatory nocifensive behavior in mice

“…The choice of bin duration and starting time to analyze Phase II vary widely across studies, for example, 10–30, 42 10–60, 14 10–90, 43 10–45, 44 15–45, 45 20–45, 36 or 20–60. 46 Bootstrapping with different bins indicates that bin choice could contribute to inconsistent results of studies if there is a temporal difference between the strains, sexes, or drug treatments of interest. The mice in this study were anesthetized which may also influence the timing of the behavior as the early part of the response is clearly reduced.…”

HINT1 in Neuropsychiatric Diseases: A Potential Neuroplastic Mediator

“…However, the dose-response curve indicated that KO mice exhibited a greater extent of tolerance to morphine-induced analgesia than WT mice. In addition, our group and Garzon's research team revealed that HINT1 deficiency could induce abnormalities in the hot-plate test, formalin-induced inflammatory pain, and CCI-induced neuropathic nociception [ 58 – 60 ]. In particular, Garzon and colleagues demonstrated that the inhibitor of HINT1 enzymatic activity, guanosine-5′-tryptamine carbamate (TpGc), significantly enhanced morphine antinociception and alleviated mechanical allodynia but prevented the development of tolerance to opioids [ 61 ].…”