Effects of Neurogenesis on Pain Behavior 1 Running Head : Effects of Neurogenesis on Pain Behavior The Relationship Between Neurogenesis and Pain Behavior

One of the most prominent discoveries of recent neuroscience is the finding that neurogenesis, the formation of new neurons, can occur in the adult brain. While it was previously thought that neurogenesis occurs only in developmental stages, recent breakthrough research has revealed novel analyses about the brain, specifically its inherent plastic nature. Plasticity is not just an attribute of the brain; many bodily mechanisms exhibit plastic properties, as well, including the pain pathway. Sensitization, or the lowered sensitivity threshold of pain-responsive receptors with increased stimulation, is one such example of plasticity in the pain response. Interestingly, mechanisms of pain and neurogenesis have been shown to be connected. Research indicates an inverse relationship between pain and neurogenesis: fewer neurons will form as pain is enhanced. Patients with Alzheimer’s disease, a disease in which adult neurogenesis occurs at a slower rate than normal, report a higher pain tolerance. The present study was designed to investigate if the administration of galantamine and nicotine, both of which are acetylcholine agonists but have opposing effects on neurogenesis, have effects on pain behavior associated with varying degrees of neurogenesis. We hypothesize that if neurogenesis increases with galantamine administration and decreases with administration of nicotine, the mice should display significantly more pain behavior in galantamine conditions when compared to both nicotine subjects and controls because of the increased number cells involved in the pain pathway that form in conjunction with new neurons. Such findings would establish a correlation between either increased pain threshold or analgesia and drug-induced neurogenesis. The general trend observed indicated that with increased neurogenesis, the subject exhibited more pain during the formalin test. Limitations and future research are discussed. Effects of Neurogenesis on Pain Behavior 3 The Relationship Between Neurogenesis and Pain Behavior One aspect of neuroscience that is well studied is the pain pathway; how one perceives, responds, and physiologically reacts to pain, as well as various factors that influence an individual’s response to pain. This paper reviews such factors, including stress, depression, and neurogenesis, the formation of new neurons in the brain. It is important to study these bodily mechanisms both independently and in relation to one another so as to best comprehend the underlying processes of these sensations. Pain has been shown to have hindering effects on adult neurogenesis, indicating a correlational relationship between new neuron formation and nociception. Furthermore, antidepressants have been demonstrated as analgesics as well as effective treatments of the side effects of Alzheimer’s disease, a disease in which neurogenesis occurs at a slower rate than normal. Patients with Alzheimer’s disease also often report a higher pain tolerance. Such findings encourage further research to determine if increased pain threshold is a direct effect of the disease itself or a bodily response to the medications that Alzheimer’s patients receive. Our experiment was designed to further investigate this connection between pain and neurogenesis by observing the effects of induced neurogenesis on subsequent pain behaviors. By utilizing Alzheimer’s medication as a means of inducing varying degrees of neurogenesis, we found a direct correlational relationship between neurogenesis and pain behavior. Such findings imply that effects on pain threshold are likely due to the properties of the disease itself rather than the medications taken to counter the disease. Pain Sternbach (1968) defines pain as an abstract notion referring to 1) a personal feeling of hurt, 2) a damaging stimulus that leads to tissue damage, and 3) a series of reactions that occur in Effects of Neurogenesis on Pain Behavior 4 order to protect the individual from further injury. There are many aspects of pain to account for when investigating this phenomenon. Pain has both a sensory component as well as an emotional component. Always an unpleasant sensation, pain involves an individual’s affective response. It is important, then, to differentiate between pain “sensation” and pain “perception. ” Sensation, the physical component, also known as nociception, is described as impending or resulting tissue damage resulting from an alteration in the activity of neurons, which, in turn, is sent as sensory information to the brain and spinal cord. Conversely, perception is the individual’s subjective experience that depends on the brain collecting information from incoming afferent neurons (Sternberg, 2007). Thus, in observing pain behaviors in an experimental setting, researchers are studying the subjective translation of incoming peripheral sensations to specific locations of pain perceived on (or in) the body. Sensation, on the other hand, can be observed using brain imaging techniques which show neural activity of the brain. Both perception and sensation are important in the study of pain, but their occurrences are not dependent on one another. An individual can experience perception with seemingly harmless sensations, as in the disorder known as allodynia (Basbaum & Jessell, 1991), and the body also can experience sensory stimulation without translating this as “pain” to the brain, as occurs during the “fight or flight” response or an adrenaline rush that produces stress-induced analgesia. In studying pain, the different types of pain that an individual can encounter are important to understand. In transient pain, there is no damage observed in the body tissue, but nociceptors are activated and pain is briefly perceived. Acute pain involves body tissue injury and activated nociceptors at the injury site. Often, the body will heal itself of acute pain with time. Chronic pain entails a possible exceeding of the body’s abilities to heal itself, and frequently emerges because of previous injury or disease. It differs from acute pain in that the Effects of Neurogenesis on Pain Behavior 5 body often is unable to replace the functions that are operating during normal homeostasis (Loeser & Melzack, 1999). There are also different types of pain sensations, which are perceived according to the type of nociceptor that is activated. Afferent nociceptors have little to no myelin, and, as a result, conduct information very slowly. Thermal nociceptors are sensitive to extreme heat or cold, while mechanical nociceptors are active with extreme pressure forced on the skin. Polymodal nociceptors react with intensive thermal, mechanical, or chemical stimulation. (Loeser & Melzack, 1999) When any one of these nociceptors’ receptors is activated, the body responds with a conversion of the sensory energy to a depolarizing electrical potential. This electrical signal is then transmitted in the nerve through the dorsal root ganglia, which contains the sensory nerve fibers known as C-nociceptors that respond to noxious stimuli. The axons of the cell bodies of the dorsal root ganglia connect by way of synapses to other cell bodies located in the dorsal horn of the spinal cord. Secondary projections, whose fibers cross the midline of the spinal cord, turn upwards and send information from the spinal cord to the thalamus in the brainstem, where it then proceeds to specific cortices with higher-order functioning (Sternbach, 1968). Additional projections target including the limbic system, which manages the emotional response to noxious stimuli (Basbaum & Jessell, 1991). It is important to note that once sensory information is relayed to the brain, the brain’s role is not only to translate this information, but it also must compare this information with stored memories containing comparable information in order to produce the appropriate, adaptive behavioral response (Melzack & Wall, 1973). A recent meta-analysis conducted by Peyron, Laurent, & Garcia-Larrea in 2000 reviewed the literature on the areas of the brain that are activated during a painful experience using Effects of Neurogenesis on Pain Behavior 6 positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) technology. Both PET and fMRI techniques measure the brain activity of awake, alert humans. Areas showing activation during acute pain include the thalamus and the anterior cingulate cortex, which also showed increased blood flow (and thus, activation), during analgesia. Allodynia revealed an activated thalamus, insular cortex, and the secondary somatosensory area. Brain imaging responses considered the emotive, cognitive, and sensory components of pain processing. The authors also suggest that a structure can simultaneously be involved in both pain response and pain inhibition. The limbic system regulates the affective response to pain (Sternberg, 2007). The cingulate gyrus and the insular cortex are also central elements in the process of pain perception. The insular cortex is involved in the autonomic, reflexive portion of the pain response, while the cingulate gyrus receives projections from the thalamus and relays these projections to the prefrontal cortex, which stores the information as pain, thus completing the input pathway (Nagai, Kishi, & Kato, 2007). The limbic system has been shown to be involved in the pain pathway in many ways. Removal of amygdala tissue has revealed decreased responsiveness to noxious stimuli, indicating an involvement of the limbic system in the affective, unpleasant component of pain (Melzack & Wall, 1973). Modulation of Pain The body is capable of preventing or delaying the perception of pain based on the surrounding environmental factors. A stressor can activate the “fight-or-flight” response, in which case the stress signal from the hypothalamus transfers downward to the midbrain, then the medulla, and finally to the spinal cord where signal-negating synapses are constructed. Ne