Identification of an Adenylyl Cyclase Inhibitor for Treating Neuropathic and Inflammatory Pain

In animal models, an adenylyl cyclase 1 inhibitor acts as an effective treatment for neuropathic pain, in part by acting on the anterior cingulate cortex. No Gain from Pain Pain from a hot stove or an injury can be a good thing. It can help to prevent more serious damage, but chronic, burning, or aching pain—also called neuropathic pain—seems to have no purpose. Analgesics that block only neuropathic pain are desirable but scarce. Wang et al. have now identified a promising new candidate by screening for drugs that selectively block a type of calcium-activated adenylyl cyclase that participates in neuropathic pain. They identify one, NB001, which can block this type of pain in rodents without apparent side effects. Adenylyl cyclase 1 has many characteristics of a good drug target for neuropathic pain: It is an activity-dependent enzyme, expressed selectively in neurons, that is critical for the pain-related neural plasticity thought to underlie this kind of pain. The authors screened chemical compounds for inhibition of cyclic AMP production and of the transcription factor CREB in human cells transfected with adenylyl cyclase 1. One of these, NB001, was most effective and also inhibited cyclic AMP production in mouse brain slices and human neurons. NB001 prevented allodynia (a condition in which an innocuous stimulus causes pain) in mice in which certain nerves were ligated or in mice with chronic inflammatory pain, produced by an injection of an irritant into a paw. And when the drug was injected directly into the anterior cingulate cortex (a brain region involved in neuropathic pain generation), it also prevented allodynia, although to a lesser extent, suggesting that NB001 acts on multiple sites in the body. Just as important as these effects of NB001 on chronic pain are the effects that it does not have. NB001 does not interfere with normal nociception, the sensation that allows the animal to escape dangerous heat. It does not affect neurotransmission of the critical hormone glutamate or the size of glutamate-induced currents. Tests of anxiety, motor function, and fear all showed that NB001 had no effects on these endpoints, a good sign for the potential safety profile of this drug. A clue to how NB001 works can be gleaned from the result that it extinguishes the ability of synapses in the dorsal horn of the spinal cord and the anterior cingulate cortex to “learn,” a process triggered in neuropathic pain. This effect may underlie its analgesic ability, a conclusion consistent with the fact that it does not alter such plasticity in the hippocampus, a non–pain-related brain region. If the selective action of NB001 on neuropathic pain and its lack of serious side effects also holds true in humans, it may prove useful to eliminating seemingly purposeless pain from our lives. Neuropathic pain, often caused by nerve injury, is commonly observed among patients with different diseases. Because its basic mechanisms are poorly understood, effective medications are limited. Previous investigations of basic pain mechanisms and drug discovery efforts have focused mainly on early sensory neurons such as dorsal root ganglion and spinal dorsal horn neurons, and few synaptic-level studies or new drugs are designed to target the injury-related cortical plasticity that accompanies neuropathic pain. Our previous work has demonstrated that calcium-stimulated adenylyl cyclase 1 (AC1) is critical for nerve injury–induced synaptic changes in the anterior cingulate cortex. Through rational drug design and chemical screening, we have identified a lead candidate AC1 inhibitor, NB001, which is relatively selective for AC1 over other adenylate cyclase isoforms. Using a variety of behavioral tests and toxicity studies, we have found that NB001, when administered intraperitoneally or orally, has an analgesic effect in animal models of neuropathic pain, without any apparent side effects. Our study thus shows that AC1 could be a productive therapeutic target for neuropathic pain and describes a new agent for the possible treatment of neuropathic pain.