Selective inhibition of adenylyl cyclase subtype 1 reduces inflammatory pain in chicken of gouty arthritis

Abstract

Lack of uricase leads to the high incidence of gout in humans and poultry, which is different from rodents. Therefore, chicken is considered to be one of the ideal animal models for the study of gout. Gout-related pain caused by the accumulation of urate in joints is one type of inflammatory pain, which causes damage to joint function. Our previous studies have demonstrated the crucial role of calcium-stimulated adenylyl cyclase subtype 1 (AC1) in inflammatory pain in rodents; however, there is no study in poultry. In the present study, we injected mono-sodium urate (MSU) into the left ankle joint of the chicken to establish a gouty arthritis model, and tested the effect of AC1 inhibitor NB001 on gouty arthritis in chickens. We found that MSU successfully induced spontaneous pain behaviors including sitting, standing on one leg, and limping after 1–3 h of injection into the left ankle of chickens. In addition, edema and mechanical pain hypersensitivity also occurred in the left ankle of chickens with gouty arthritis. After peroral administration of NB001 on chickens with gouty arthritis, both the spontaneous pain behaviors and the mechanical pain hypersensitivity were effectively relieved. The MSU-induced edema in the left ankle of chickens was not affected by NB001, suggesting a central effect of NB001. Our results provide a strong evidence that AC1 is involved in the regulation of inflammatory pain in poultry. A selective AC1 inhibitor NB001 produces an analgesic effect (not anti-inflammatory effect) on gouty pain and may be used for future treatment of gouty pain in both humans and poultry.

Human safety study of a selective neuronal adenylate cyclase 1 inhibitor NB001 which relieves the neuropathic pain and blocks ACC in adult mice

“…These results of hNB001 are in consistent with previous animals' studies using NB001 which is designed for research tool in the lab. [12][13][14]17,28,31 With dose escalation, the exposure of hNB001 increased proportionally, suggesting linear PK. Before the start of this study, the HED of hNB001 20 mg/kg in rats was estimated to be approximately 200 mg for a man with 60 kg body weight.…”

“…Recent studies have also demonstrated the analgesic effect of NB001 on animal models of gouty arthritis, migraine, and Parkinson's disease-related pain. [17][18][19][20] The analgesic effect of NB001 is believed to be produced by inhibiting several central synaptic mechanisms that are critical for chronic pain and related emotional changes. 21 They include the following: cortical postsynaptic long-term potentiation (post-LTP) and presynaptic long-term potentiation (pre-LTP) in the ACC and IC, 5 activation of various immediate early genes, 22,23 upregulation of NMDA receptors 24 after injury, new protein synthesis of AC1 after injury, 15 spinal LTP and serotonin-induced facilitation.…”

A Review of the Emerging Poultry Visceral Gout Disease Linked to Avian Astrovirus Infection

“…It is reported that adenylyl cyclase subtype 1 (AC1) is involved in the regulation of gouty pain in chickens. A selective AC1 inhibitor NB001 produces an analgesic effect (not anti-inflammatory effect) on gouty pain and may be used for the future treatment of gouty pain in both humans and poultry [ 57 ].…”

“…Research on avian coronavirus found that a significant increase in xanthine oxidase (XOD) activity in serum and a significant increase in serum uric acid levels were related to nephropathogenic IBV infection with increased uric acid synthesis and inhibited peroxisome functions [ 67 ]. It has been reported that the NMDAR-AC1-TRPA1 pathway may participate in the regulation of gouty pain in chickens [ 57 ]. For gout in goslings, young goslings are high-risk groups of visceral gout.…”

Reduced activity of adenylyl cyclase 1 attenuates morphine induced hyperalgesia and inflammatory pain in mice

“…The inhibition of AC1 could also help attenuate pain sensitization beyond the primary zone of injury through changes in functional plasticity that occurs in contralateral sensory nerves following the induction of inflammation (Kelly et al, 2007) that may not follow the same time course as the ipsilateral side. AC1 inhibition most likely does not impact the progression of inflammation directly, as other studies have shown that NB001, does not impact CFA-Frontiers in Pharmacology frontiersin.org induced knee joint structural destruction nor mono-sodium urateinduced edema of the ankle joint (Tian et al, 2015;Liu et al, 2021). Alternatively, those results may be explained by the smaller overall level of the Adcy1 knockdown in our studies when compared to global AC1 knockout mice (Wei et al, 2002).…”