No description available.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The purpose of this research was to determine, using the 2[14C]deoxyglucose autoradiographic method, the local cerebral metabolic rates for glucose (LCMRglu) after the administration of morphine or saline in rats escaping from acute or chronic footshock or exposed to conditioned stress. All animals were given morphine (4mg/kg, sc) or saline 7 days, 3 days and 10 minutes prior to the tracer injection. The effects of stimulation in the acute and chronic footshock studies revealed that an identical noxious stimulus may not have similar effects on functional cerebral activity if there are differences in experience with the str1xsor. The results of the conditioned stress experiment demonstrate that simply placing an animal in an environment previously associated with footshock is sufficient to elicit changes in LCMRglu. The effects of morphine in the control and acute footshock experiments were similar in that nearly all of the 73 analyzed brain regions (99% and 93%, respectively) showed decreases in LCMRg1u. Morphine, however, caused fewer decreases (56%) in the chronic footshock study. Interestingly, the percentage of structures showing decreases in the conditioned stress study (79%) was approximately halfway between the effects seen in the two footshock studies. Morphine in the presence of acute footshock, compared to acute footshock alone, caused significant decreases in elements of the limbic telencephalon, basal forebrain and thalamic midline (paraventricular and paratenial nuclei). On the other hand, morphine did not cause any significant decreases in these structures (or others) in the chronic footshock study. Rather, the combination of morphine and chronic footshock, compared to morphine alone, caused significant increases in several brainstem structures previously implicated in opioid analgesia: the locus coeruleus, gigantocellular reticular nucleus and raphe magnus. Additionally, significant effects were seen in basal ganglia structures which are normally associated with the motor system. The effects seen in these structures, along with the significant effect demonstrated in the parafasicular thalamic nucleus, suggest that morphine works to attenuate pain in animals exposed to chronic footshock via neural networks responsible for sensorimotor reactions to pain. Alternatively, animals exposed to chronic footshock may have developed tolerance to the effects of morphine. The effects of morphine, however, in the chronic footshock experiment are much different from those seen in the acute footshock study where morphine acts primarily in limbic structures and midline thalamus to attenuate the affective reaction to pain. / 2999-01-01

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Pharmacology / Doctoral / Doctor of Philosophy

published_or_final_version / Biochemistry / Master / Master of Science

published_or_final_version / Pharmacology / Master / Master of Philosophy

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

No description available.

No description available.

P2X7 receptors belong to a family of membrane bound ion channels which are activated by extracellular ATP, resulting in the opening of a non-selective cation channel. After prolonged or repeated exposure to agonist, functional and cellular changes can occur, including the formation of a large pore, cell lysis and the release of mature, biologically active interleukin-1β. It is this diversity of functions that underlies the significance of this receptor in pain processing. P2X7 receptors are expressed on microglia, which when activated, release a host of mediators which contribute to central sensitisation, a phenomenon associated with neuropathic pain. The role of P2X7 receptors in the activation of microglia is less well established and is the main subject of this thesis. Before considering the interaction between P2X7 receptors and microglia, the first aim was to establish whether P2X7 receptors played a role in a pathological process known to be associated with microglial activation. An additional aim was to establish whether the site of action was in the central nervous system (CNS), where microglia are located. These aims were accomplished using a surgery-based rat model of neuropathic pain, the chronic constriction injury (CCI) model, and by comparing the effects of different P2X7 receptor antagonists when dosed peripherally or directly into the spinal cord. The results indicated that P2X7 receptor antagonists produced efficacy in the CCI model via a mechanism located in the CNS. To further investigate the association between P2X7 receptors and microglia, a different experimental paradigm was explored. Chronically dosed morphine is known to activate microglia, the consequence of which is thought to underlie morphine tolerance and reduced morphine analgesia. By administering a P2X7 receptor antagonist to CCI-operated rats treated with chronic morphine, the interaction between the P2X7 receptor and morphine tolerance and analgesia was explored. The results showed that P2X7 receptor antagonism delayed morphine tolerance and increased the efficacy of low doses of morphine, suggesting an association between P2X7 receptors and microglia. It was intended to confirm the interaction between a P2X7 receptor antagonist and morphine in another neuropathic pain model, namely varicella zoster virus-induced neuropathy. However due to a lack of reproducibility, this model was not used for pharmacological studies. Having demonstrated an association between P2X7 receptor antagonist and morphine in a chronic pain setting, studies were initiated to explore whether this interaction occurred in other morphine-related behaviours. The effect on body weight, motor coordination and single dosed morphine-induced analgesia was assessed in rats co-administered with P2X7 receptor antagonist and morphine. Results demonstrated that the blockade of P2X7 receptors enhanced morphine acute dose-induced analgesia, but had no influence on motor-impairment and body weight. The final part of the thesis used immunohistochemical and molecular techniques to confirm that microglia played a role in established allodynia induced by CCI-surgery and that P2X7 receptors directly influenced microglia-activation. In conclusion, the data in this thesis has illustrated an association between centrally activated P2X7 receptors and microglia, as well as an association between the P2X7 receptor and morphine-induced tolerance and analgesia. It is possible that co-administration of a P2X7 receptor antagonist with morphine could reduce the effective dose of morphine clinically, thereby reducing the side effects of this commonly used analgesic.