thermal or mechanical stimuli (Ren and Dubner, 1993). Methods of measuring nocifensive behavior have also been applied to the orofacial region (Imamura et al., 1997; Ren and Dubner, 1993). In the above studies, most of the nocifensive behaviors provide an animal with control of the intensity or duration of the stimulus in that the behaviors result in removal of the aversive stimulus.

Animals in persistent-pain models do not have control of stimulus intensity or duration. For example, the writhing response is produced in rodents by injecting pain-producing chemical substances intraperitoneally. The acute peritonitis resulting from the injection produces a response characterized by internal rotation of one foot, arching of the back, rolling on one side, and accompanying abdominal contractions. The writhing response is considered a model of visceral pain (Vyklicky, 1979). Not only does the animal lack stimulus control with this method, but the experimenter cannot control the duration of the stimulus. In another test, formalin is injected beneath the footpad of a rat or cat (Abbott et al., 1995; Dubuisson and Dennis, 1977). The chemical produces complex response patterns that last for about an hour. Many response measures are used for assessing pain after formalin injection. They include single measures such as flinching, shaking, and jerking—or complex scores that are derived from several nocifensive behaviors, such as licking or guarding (Clavelou et al., 1995). However, the animals do not have complete control over the aversiveness of the persistent stimulus. Vocalization is another common, unlearned reaction to painful stimuli (Kayser and Guilbaud, 1987), and the stimulus intensity necessary to elicit a vocal response from the animal can be determined. The stimulus can be applied to any part of the body; again, the animals cannot control the intensity or duration of the stimulus.

Nerve-injury models that mimic neuropathic pain in humans have been developed recently (Dubner and Ren, 1999). Partial nerve injury in the rat results in signs of hyperalgesia and spontaneous pain. In one model, loose ligatures are placed around the sciatic nerve; demyelination of the large fibers and destruction of some unmyelinated axons result (Bennett and Xie, 1988). In another model, ligation and severing of the dorsal one-third to one-half of the sciatic nerve produce similar behavioral changes (Seltzer et al., 1990). Kim and Chung (1992) have developed a third model, in which the L5 and L6 spinal nerves are tightly ligated on one of the rat’s sides. All three models mimic clinical conditions of painful neuropathy and yield evidence of persistent spontaneous pain, allodynia (pain resulting from a nonnoxious stimuli), and hyperalgesia. These nerve-injury models of neuropathic pain have been adapted for use in mice (Malmberg et al., 1997; Ramer et al., 1997), in which they can be used to study pain mechanisms in transgenic models.

Ethical Considerations Associated with Pain Research

Anesthetic and pain-relieving methods and drugs generally act on the system under study—the nervous system—and neuroscientists and IACUCs must make

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