The most pervasive and universal form of human distress is pain. It has an inverse relationship with one’s quality of life [1, 2] and negatively impacts collective social productivity [3]. Pain is one of the most common reasons for a visit to a physician’s office, community health center, and emergency rooms and is now considered the fifth vital sign. When pain interferes with and at times halts the activities of one’s daily activities, pain becomes central to that person’s daily existence.

While most acute pain can be easily treated and is essential for disease diagnosis, conversion to a chronic pain condition often becomes more difficult to treat and retains little value in terms of identification of pending damage, dysfunction, or disease. Such chronic pain conditions become challenging to treat for a variety of reasons. First, chronic pain can arise from a wide variety of central or peripheral nervous system dysfunctions such as inflammation, neuropathy, disease specific, or related to cancer. In many cases, the pain is caused by multiple points of dysfunction. Such conditions are often difficult to treat pharmacologically [4–6] for reasons associated both with the neurobiology of pain and the chemistry of pharmacological agents used to treat pain. Specifically, chronic pain of differing etiology may evoke differential neurochemical and molecular changes at multiple levels of the central nervous system [7]. These alterations often occur at the neurotransmitter (e.g., endorphins, substance P, glutamate, etc.) and/or receptor (e.g., opioid, neurokinin, glutamate receptors, etc.) levels. The complexity of pain processing systems presents a challenge for pharmacological interventions for pain relief. For this reason, there currently are fairly limited options for pharmacological treatments for chronic pain. That is an area of universal disappointment for pain researchers, industry, practitioners, patients, and their families.

The primary and most effective class of pharmacological agents used to manage chronic pain remains the opioid agonists. Opioid receptors are inhibitory G protein-coupled receptors expressed at nearly every point in the pain signal conduction pathway (primary afferent peripheral nerve terminal, primary afferent spinal terminal, second order neurons, rostral ventral medulla, periaqueductal gray, and thalamus). Therefore, they are well positioned to regulate the pain signal and appear to be the most effective target for this purpose. Consequently, opioids have been used for centuries to control pain. However, opioid receptors are also expressed in brain regions that control emotion and reward, which can be dysregulated with chronic drug exposure and lead to drug dependence and addictive behavior.

For many years, the claim was made that chronic pain patients, who take opioid medication for treatment of their pain, self-administer the drug to attain the analgesic effect and rarely become addicted [8]. It was on that basis that prescribers have been increasingly educated and retrained to appropriately treat patients for their pain, which is often undertreated; it has been asserted that only 25 % percent of chronic pain patients receive adequate treatment [9]. Concerns were raised regarding practitioner bias against prescribing opioids starting at the level of medical school students [2] and other health professionals such as pharmacists and regulators [10]. It is noteworthy that among medical board regulators, the perceived legal and medical acceptability of treating patients with a history of opioid misuse, even for cancer-related pain, was significantly reduced relative to patients without a history of misuse [10]. The introduction of sustained-release opioids to the pain management armamentarium in the 1990s provided extensive initial enthusiasm [11] in terms of improved pharmacokinetics in that these new sustained-release formulations offered serum levels of opioids that could be maintained at steady state for 12–24 h. Such a pharmacokinetic profile meant that patients needing chronic pain management would be at significantly less risk for breakthrough pain associated with opioid regimens reflecting shorter half-lives that result in more frequent drops in serum levels below the minimal effective concentrations [11]. Therefore, the introduction of sustained-release opioid medications was considered a significant advance in treatment. However, concern regarding opioid therapy for pain management is still controversial for at least two reasons: the continued perceived misuse of opioids and the lack of efficacy in nonmalignant pain management.

It remains unclear whether there is a biological basis for restricting the use of opioids in patients with chronic pain, particularly of nonmalignant origin. The National Institutes of Health (NIH) has recently acknowledged this problem and has attempted to address this issue by developing research programs specifically to investigate the relationship of prescription opioid use and misuse, CNS changes that occur with chronic pain, and how these changes parallel those that occur with drug addiction. In 2005 and 2008, requests for applications were announced by NIH that specifically addressed these issues with an emphasis on clinical research in the first case Prescription of Opioid Use and Abuse in the Treatment of Pain (NIDA/NIA/NIDCR) and an emphasis on basic research in the second case Central Nervous System Intersections of Drug Addiction, Chronic Pain and Analgesia (NIDA/NINDS).

Research investigating the effectiveness of morphine in neuropathic pain patients showed that morphine was not effective in certain forms of neuropathic pain [12]. However, this study was limited in scope in terms of patient population and dosing schedule. The patients received two doses of 10–20 mg morphine i.v. and were only evaluated 15 min following infusion. In addition, these patients suffered from severe neuropathic pain that had been unresponsive to nerve block, surgery, transcutaneous electrical nerve stimulation (TENS), and drug therapy including other opioids such as buprenorphine and pentazocine. The overall conclusions of the 1988 study are still used to support the argument against use of opioids for neuropathic pain; yet, these results have been challenged by many preclinical and clinical trials [13–15].

Using an animal model of neuropathic pain, La Buda and colleagues examined the efficacy of several pharmacological agents that are used for treatment of neuropathic pain. They found that the nonopioid drug gabapentin, which interacts with voltage-gated calcium channels and increases synaptic availability of γ-aminobutyric acid (GABA), reversed spinal nerve ligation (SNL)-induced neuropathic pain with complete efficacy [14].

Several reports have contributed to the growing acceptance of the assertion that patients with noncancer pain may achieve good pain control from opioid therapy [16]. However, there is also consensus that the current clinical literature on opioid use for the treatment of noncancer pain does not address issues of long-term opioid maintenance and that such studies are critical to inform management plans for treatment of noncancer chronic pain patients with opioid therapy [17, 18].

To provide an evidence-based animal model framework to move the field forward, this chapter discusses the animal models that are used to quantitatively measure nociception and analgesia, and animal models that are used to study inflammatory, neuropathic, and visceral pain. We also discuss the animal models used to study opioid dependence. Finally, we discuss how the use of models of chronic pain and opioid dependence can increase our knowledge on the neurobiology of the association of chronic pain and drug addiction.

Many models have been developed to mimic human conditions and to study pain and its underlying mechanisms in whole animal systems. These models allow for quantitative and qualitative measurements and examination of alterations of the physiology during the chronic pain state. Animal models of chronic pain are used to (1) induce a pain state that mimics common human conditions of pain, (2) quantitatively characterize the degree of pain resulting from the injury, (3) evaluate mechanisms responsible for pain, and (4) evaluate analgesic efficacy directed toward alleviation of the injury.

Animal models of pain include models of hyperalgesia, defined as increased sensitivity toward painful stimuli and models of allodynia in which normally nonnoxious stimuli are perceived as painful. These models are used to study neuroadaptive changes associated with chronic pain. These measurements, which are the dependent variables, are generally quantified as a deviation from the normal baseline threshold in each animal before induction of injury and the resulting pain. Following administration of potential analgesics measurements assessing hyperalgesia or allodynia can be taken again to evaluate the efficacy and potency of the analgesic of interest.

Hyperalgesia or allodynia can be examined using a variety of models that measure force applied to the affected area or time to withdraw the paw when exposed to a stimulus. It is important to consider the model of pain when choosing the method of hyperalgesia assessment. While hyperalgesia resulting from inflammation can effectively be assessed using mechanical, thermal, and static models, there has been mixed reviews regarding assessment of neuropathic pain. Most often neuropathic pain is assessed using mechanical stimuli and there has been limited data supporting the use of thermal hyperalgesia to assess neuropathic pain. An overview of common measurements is described below.

There are several animal models (the independent variables) utilized to produce a state of hyperalgesia that mimic common ailments such as inflammation (arthritis, burns, and Crohn’s disease, and other causes of acute or chronic inflammation) or neuropathic pain resulting from physical trauma, diabetes, chemotherapy, or from other etiologies. The use of these models has led to many insights regarding the physiology of specific pain states, receptor regulation, and possible treatments.

Animal models of inflammation have taught us important aspects of inflammatory pain that are specific to inflammation and different than pain arising from other origins such as nerve injury. Valuable information regarding recruitment of inflammatory mediators that result in chronic pain and upregulation of sensory transduction mechanisms that lead to sensitization in the periphery and central nervous system have also led to a deeper understanding of how to treat pain from an inflammatory origin. Several receptors respond to inflammation and contribute to hyperalgesia and sensitization. Below we describe the most common animal models of inflammation.

Neuropathic pain is pain that originates from the nerves due to actual or perceived damage (International Association for the Study of Pain). Neuropathic pain can commonly arise from physical trauma, disease states such as diabetes, and as a result of treatment for other diseases, most commonly in conjunction with cancer chemotherapeutics. Tissue damage contributing to neuropathic pain can have lasting effects, following apparent recovery, to the surrounding nerves, which can severely impact quality of life and mobility. In general, neuropathic pain results in allodynia defined as where nonpainful stimuli or activity such as brush or movement become painful. During a neuropathic pain state, there is upregulation of several proinflammatory cytokines and increases in glutamatergic transmission that lead to sensitization of pain pathways.

Because of the unique nature of neuropathic pain, reliable and quantifiable models of neuropathic pain were developed. Each of the described models has unique profiles of nociception. SNL and partial nerve injury result in robust mechanical allodynia whereas chronic constriction injury (CCI) is more sensitive in thermal and cold nociception assays [27]. One specific advantage of these models is that the allodynia is contained to the side of the injured nerve, leaving the contralateral paw unaffected. This allows for a within subject control when evaluating possible analgesics.

Opioid abuse and dependence are major public health problems. According to the Substance Abuse and Mental Health Services Administration (2010), the number of people dependent on or abusing pain relievers increased between 2002 (1.5 million) and 2009 (1.9 million). Therefore, a major need exists for research into the neurobiology of opioid addiction with the hope of developing better strategies for the treatment of opioid dependence. Treatment options to date are largely limited to substitution-therapy with the use of long-lasting opioid drugs, such as methadone and buprenorphine, or limited use of α2-adrenergic agonists, such as clonidine [37, 38], which all have pronounced adverse effects.

Although addiction (or drug dependence as defined by the Diagnostic and Statistical Manual of the American Psychiatric Association) [39] is a typical human condition, physiological, psychological, and behavioral phenotypes have been described in several animal species and are thought to be analogous to human addiction. Depending on the scientific question to be investigated different models can be used to assess different aspects of drug dependence (e.g., intoxication, withdrawal, relapse, physical dependence, etc.). Here, we describe some of the most commonly animal models used in the addiction field with emphasis on intravenous (IV) self-administration.