Small Molecule Angiotensin II Type 2 Receptor (AT2R) Antagonists as Novel Analgesics for Neuropathic Pain: Comparative Pharmacokinetics, Radioligand Binding, and Efficacy in Rats

Pain Medicine

1. Maree T. Smith PhD^1,2,*, 
2. Bruce D. Wyse PhD^1,2, 
3. Stephen R. Edwards PhD^1,2

Article first published online: 14 MAR 2013

DOI: 10.1111/pme.12063

Abstract

Objective

Neuropathic pain is an area of unmet clinical need. The objective of this study was to define the pharmacokinetics, oral bioavailability, and efficacy in rats of small molecule antagonists of the angiotensin II type 2 receptor (AT₂R) for the relief of neuropathic pain.

Design and Methods.

Adult male Sprague-Dawley (SD) rats received single intravenous (1–10 mg/kg) or oral (5–10 mg/kg) bolus doses of EMA200, EMA300, EMA400 or EMA401 (S-enantiomer of EMA400). Blood samples were collected immediately pre-dose and at specified times over a 12- to 24-hour post-dosing period. Liquid chromatography tandem mass spectrometry was used to measure plasma drug concentrations. Efficacy was assessed in adult male SD rats with a unilateral chronic constriction injury (CCI) of the sciatic nerve.

Results.

After intravenous administration in rats, mean (±standard error of the mean) plasma clearance for EMA200, EMA300, EMA400, and EMA401 was 9.3, 6.1, 0.7, and 1.1 L/hour/kg, respectively. After oral dosing, the dose-normalized systemic exposures of EMA400 and EMA401 were 20- to 30-fold and 50- to 60-fold higher than that for EMA300 and EMA200, respectively. The oral bioavailability of EMA400 and EMA401 was similar at ∼30%, whereas it was only 5.9% and 7.1% for EMA200 and EMA300, respectively. In CCI rats, single intraperitoneal bolus doses of EMA200, EMA300, and EMA400 evoked dose-dependent pain relief. The pain relief potency rank order in CCI rats was EMA400 > EMA300 > EMA200 in agreement with the dose-normalized systemic exposure rank order in SD rats.

Conclusion.

The small molecule AT₂R antagonist, EMA401, is in clinical development as a novel analgesic for the relief of neuropathic pain.

Acupuncture modulates temporal neural responses in wide brain networks: evidence from fMRI study

Molecular Pain 2010, 6:73

doi:10.1186/1744-8069-6-73(Open Access)

Lijun Bai¹ , Jie Tian^1,2 , Chongguang Zhong¹ , Ting Xue² , Youbo you¹ , Zhenyu Liu¹ , Peng Chen³ , Qiyong Gong⁴ , Lin Ai⁵ , Wei Qin² , Jianping Dai⁵  and Yijun Liu^6,7 

¹ Medical Image Processing Group, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China

² School of Life Science and Technology, Xidian University, Xi'an 710071, China

³ Beijing TCM Hospital affiliated to Capital University of Medical Sciences, Beijing 10010, China

⁴ West China Hospital of Sichuan University, Sichuan 610041, China

⁵ Department of Radiology, Beijing Tiantan Hospital, Capital University of Medical Sciences, Beijing, 100050, China

⁶ McKnight Brain Institute, Departments of Psychiatry and Neuroscience, University of Florida, Gainesville, FL 32610, USA

⁷ Department of Biomedical Engineering, Peking University, Beijing 100871, China

Published:	2 November 2010

Abstract

Background

Accumulating neuroimaging studies in humans have shown that acupuncture can modulate a widely distributed brain network, large portions of which are overlapped with the pain-related areas. Recently, a striking feature of acupuncture-induced analgesia is found to be associated with its long-last effect, which has a delayed onset and gradually reaches a peak even after acupuncture needling being terminated. Identifying temporal neural responses in these areas that occur at particular time -- both acute and sustained effects during acupuncture processes -- may therefore shed lights on how such peripheral inputs are conducted and mediated through the CNS. In the present study, we adopted a non-repeated event-related (NRER) fMRI paradigm and control theory based approach namely change-point analysis in order to capture the detailed temporal profile of neural responses induced by acupuncture.

Results

Our findings demonstrated that neural activities at the different stages of acupuncture presented distinct temporal patterns, in which consistently positive neural responses were found during the period of acupuncture needling while much more complex and dynamic activities found during a post-acupuncture period. These brain responses had a significant time-dependent effect which showed different onset time and duration of neural activities. The amygdala and perigenual anterior cingulate cortex (pACC), exhibited increased activities during the needling phase while decreased gradually to reach a peak below the baseline. The periaqueductal gray (PAG) and hypothalamus presented saliently intermittent activations across the whole fMRI session. Apart from the time-dependent responses, relatively persistent activities were also identified in the anterior insula and prefrontal cortices. The overall findings indicate that acupuncture may engage differential temporal neural responses as a function of time in a wide range of brain networks.

Conclusions

Our study has provided evidence supporting a view that acupuncture intervention involves complex modulations of temporal neural response, and its effect can gradually resolve as a function of time. The functional specificity of acupuncture at ST36 may involve multiple levels of differential activities of a wide range of brain networks, which are gradually enhanced even after acupuncture needle being terminated.

Predicting Value of Pain and Analgesia: Nucleus Accumbens Response to Noxious Stimuli Changes in the Presence of Chronic Pain

Neuron, Volume 66, Issue 1, 149-160, 15 April 2010  | 
Marwan N. Baliki,Paul Y. Geha,Howard L. Fields,A. Vania Apkarian

• • Copyright © 2010 Elsevier Inc. All rights reserved.  |  10.1016/j.neuron.2010.03.002
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  • Highlights
  • NAc predicts the reward value for expected pain relief in healthy subjects
  • NAc predicts the salience or arousal for imminent pain
  • Pain relief causes distinct NAc activities in healthy versus chronic pain subjects
  Summary
• We compared brain activations in response to acute noxious thermal stimuli in controls and chronic back pain (CBP) patients. Pain perception and related cortical activation patterns were similar in the two groups. However, nucleus accumbens (NAc) activity differentiated the groups at a very high accuracy, exhibiting phasic and tonic responses with distinct properties. Positive phasic NAc activations at stimulus onset and offset tracked stimulus salience and, in normal subjects, predicted reward (pain relief) magnitude at stimulus offset. In CBP, NAc activity correlated with different cortical circuitry from that of normals and phasic activity at stimulus offset was negative in polarity, suggesting that the acute pain relieves the ongoing back pain. The relieving effect was confirmed in a separate psychophysical study in CBP. Therefore, in contrast to somatosensory pathways, which reflect sensory properties of acute noxious stimuli, NAc activity in humans encodes its predicted value and anticipates its analgesic potential on chronic pain.