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Effects of Nicotinic Acetylcholine Receptor Agonists in Assays of Pain-Stimulated and Pain-Depressed Behavior in Rats

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Though a host of analgesics have been developed to alleviate pain, especially acute pain, significant side effects and a lack of long-term efficacy have encouraged research attempts to pursue novel targets that may be associated with fewer side effects or a more sustained efficacy. Among these new targets are members of the nicotinic family of acetylcholine receptors (nAChRs). The non-selective nAChR agonists nicotine and epibatidine have been shown to function as potent antinociceptive drugs in many acute and chronic preclinical trial models, while nicotine has produced analgesic effects in humans. However, these non-selective nAChRs agonists also produce various side effects, including gastrointestinal and cardiovascular complications that limit clinical utility. To reduce these side effects, recent research has focused on evaluating the potential role of specific nAChR subtypes in the modulation of nociception. Traditionally, assays of pain-stimulated behaviors, or behaviors that increase in rate, frequency or intensity after presentation of a noxious stimulus, have been used to evaluate nAChR agonists and other classes of candidate analgesics pre-clinically. However, clinically relevant pain states are often associated with the depression of behavior; for example in humans, pain is often accompanied by impaired function in daily activities and depression of mood. To address these depressant manifestations of pain, novel preclinical assays have been developed to assess the expression and pharmacological modulation of pain-depressed behaviors, or behaviors that decrease in rate, frequency or intensity after presentation of a noxious stimulus.

Additionally, the effects of nAChR agonists in preclinical assays of pain-depressed behavior are unknown. In assays of pain-stimulated behavior, agonism of ?4?2* receptors appears to play a prominent role in antinociception produced by drugs that target nAChRs. Recent research suggests that ?7 nAChR subtype might be an alternative target. Accordingly, the primary goal of this dissertation was to compare antinociceptive effects of the nAChR agonist nicotine and more selective nicotinic agonists in assays of pain-stimulated and pain-depressed behavior. Results from this body of work show that both nicotine and the more selective ?4?2* agonist 5-I-A-85380 produced antinociception in both types of assays, whereas an ?7 agonist did not. Taken together, these results suggest that ?4?2* nAChR agonists may be especially effective to treat signs of pain-related behavioral depression; however nonselective behavioral effects of these compounds may contribute to apparent antinociception. Studies of nAChR agonist effects on pain-depressed behavior were conducted using an assay of intracranial self-stimulation (ICSS) as a baseline behavior that is depressed by noxious pain stimuli, and pain-related depression of ICSS can be selectively alleviated by clinically effective analgesics.

As a prelude to studies of nAChR agonist effects on pain-related depression of ICSS, a preliminary study was conducted to assess effects of nicotine and 5-I-A-85380 on ICSS in the absence of a noxious stimulus. These studies indicated that selective ?4?2* agonists may have higher abuse potential than nicotine. Additionally, cognitive function is one domain of behavior that may be impaired by pain, and nAChR agonists are used to treat cognitive impairment produced by other non-pain pathologies. Accordingly, a final goal of this project was to develop an assay of pain-related cognitive impairment in rats that could be used to evaluate effects of nAChR agonists. Although results of this study did provide evidence for pain-related impairment of cognition, the effects of the pain stimuli were sufficiently variable and transient to make this procedure impracticable for use in studies with nAChR agonists.

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