Perspectives in Pharmacology Preclinical Assessment of Candidate Analgesic Drugs: Recent Advances and Future Challenges

In analgesic drug development, preclinical procedures are widely used to assess drug effects on pain-related behaviors. These procedures share two principal components: 1) a manipulation intended to produce a pain-like state in the experimental subject and 2) measurement of behaviors presumably indicative of that pain state. Drugs can then be evaluated for their ability to attenuate pain-related behaviors. In the simplest procedures, the pain state is produced by delivery of an acute noxious stimulus (e.g., a warm thermal stimulus), and the primary dependent measures focus on withdrawal responses or other nocifensive behaviors that increase in rate, frequency, or intensity in response to the noxious stimulus. This approach has been refined in two ways. First, new methods have been developed to induce more clinically relevant pain states. In particular, pain requiring clinical intervention is often associated with inflammation or neuropathy, and novel procedures have emerged to model these conditions and their ability to produce hypersensitive pain states, such as allodynia and hyperalgesia. Second, studies are incorporating a broader array of painrelated behaviors as dependent measures. For example, pain not only stimulates nocifensive behaviors but also suppresses many adaptive behaviors, such as feeding or locomotion. Measures of pain-suppressed behaviors can provide new insights into the behavioral consequences of pain and the effects of candidate analgesics. In addition, functional magnetic resonance imaging has emerged as a noninvasive tool for investigating changes in neural activity associated with pain and analgesia. Integration of these complementary approaches may improve the predictive validity of analgesic drug development. Pain is a pervasive public health problem, and analgesic drugs play a central role in its treatment. Historically, the most widely used analgesics have included -opioid agonists such as morphine, anti-inflammatory steroids such as cortisone, and nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin. Although these drugs are useful across a wide range of conditions, they are not uniformly effective, and undesirable side effects often limit their use. Consequently, one long-standing focus of drug discovery has been the search for novel analgesics. Meaningful research on pain and analgesia depends on the development of validated procedures for identifying the presence of pain and quantifying its magnitude. Pain has been defined by the International Association for the Study of Pain (1979) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”. Analgesia is a selective reduction in pain without altering sensitivity in other sensory modalities. Thus, pain and analgesia are essentially subjective experiences, and their existence in humans is typThis work was supported in part by National Institute on Drug Abuse Grant RO1-DA11460 (to S.S.N.) and National Institutes of Health, NINDS Grants R01-DA15205 (to T.W.V.) and R01-NS042721 (to D.B.). This commentary is based on a symposium presented at the 2005 Experimental Biology Meeting; 2006 Apr 2–6; San Diego, CA. American Society of Biochemistry and Molecular Biology, Washington, DC. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.106.106377. ABBREVIATIONS: NSAID(s), nonsteroidal anti-inflammatory drugs; fMRI, functional magnetic resonance imaging. 0022-3565/06/3192-507–514$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 319, No. 2 Copyright © 2006 by The American Society for Pharmacology and Experimental Therapeutics 106377/3132300 JPET 319:507–514, 2006 Printed in U.S.A. 507 at A PE T Jornals on A ril 0, 2017 jpet.asjournals.org D ow nladed from ically assessed using verbal reports. However, verbal reports are obviously not suitable for measuring pain and analgesia in animals, and this presents a challenge to preclinical research. How does one tell if an animal is in pain, and how does one tell if a candidate analgesic is effective in reducing that pain? Assays of Acute Nociception All procedures used in analgesic drug development share two principal components: 1) a manipulation intended to produce a pain-like state in the experimental subject and 2) measurement of behaviors presumably indicative of that pain state. For nearly a century, preclinical researchers interested in such issues as the genetics, neurobiology, and pharmacology of pain and analgesia have focused largely on withdrawal responses or other nocifensive behaviors that increase in rate, frequency, or intensity following the presentation of an acute noxious stimulus (Barbour and Maurer, 1920; Dykstra, 1985; Bennett, 2001; Le Bars et al., 2001; Mogil et al., 2001). The radiant-heat tail-flick test exemplifies this approach (D’Amour and Smith, 1940). In this procedure, which was based on methods originally used in humans, a rat’s tail is placed beneath a radiant heat source (i.e., a light bulb), the heat source is activated, and the primary dependent variable is the latency to tail withdrawal. Rapid tail withdrawal is considered evidence of “nociception” (i.e., the ability to detect a noxious stimulus), and nociception is thought to be functionally related to pain. Attenuation of the tail-withdrawal response by drugs is considered preliminary evidence of “antinociception,” which is thought to be related