Considerable evidence suggests the involvement of the ventrolateral periaqueductal gray (PAG) in both inhibitory and facilitatory actions within modulatory pathways for pain, The PAG is a critical nucleus in these pain networks and receives and sends extensive projections within these networks. Chronic pain is a major side effect in 30-70% of cancer patients receiving chemotherapeutic regimen. Endocannabinoids, such as anandamide (AEA), are lipid neuromodulators in the CNS that affect nociception. AEA is known to activate cannabinoid (CB1) as well as transient receptor potential vanilloid 1 (TRPV1) receptors, which are involved in nociception. Previous studies have shown that PAG is a crucial site for EC- mediated analgesia. Hypothesis one of my project is blockade of AEA uptake in the PAG will induce analgesic effects, which are mediated by CB1 and/or TRPV1 receptors. My results indicate that focal bilateral microinjection of AM404, an AEA uptake inhibitor, into the PAG induced analgesia to noxious thermal stimuli (radiant heat) both in normal and paclitaxel-treated (2 mg/kg i.p. for 4 alternate days). This analgesia was mainly mediated by both CB1 and TRPV1 receptors in the PAG in normal and by CB1 receptors in paxlitaxel-treated rats. Several studies have demonstrated that post-ictal analgesia is observed following drug-induced generalized seizures in rats. My second hypothesis is that post-ictal analgesia will occur after audiogenic seizure (AGS) induction, in genetically epilepsy prone rats (GEPR-9s), and blockade of CB1 receptors in the PAG will inhibit the analgesic effects that occur during the post-ictal period. My results indicate that induction of AGS resulted in post-ictal analgesia in GEPR-9s to noxious thermal stimuli, which was blocked upon microinjection of a CB1 receptor antagonist into the PAG suggesting a crucial role of PAG in post-ictal analgesia in GEPR-9s. Hypothesis three of my project is that, neuroplastic changes will occur in the PAG, leading to increases in neuronal firing during neuropathic pain, which will be altered by analgesic drugs. To evaluate this hypothesis, I studied the firing pattern of PAG neurons in awake behaving rats to noxious thermal stimuli. This involved evaluation of extracellular single unit activity using 8 channel microwire electrodes chronically-implanted in the PAG of unrestrained awake rats and examining responses to noxious thermal stimulation (Peltier device). The results indicate the presence of the three types of neuronal populations in the PAG that exhibit either "excitatory" or "Inhibitory" responses or were "non-responsive", to noxious thermal stimulus administered to the paw. Subsequently, I also investigated effects of pentobarbital on spontaneous and thermal stimulus evoked PAG neuronal firing, as has often been done in previous pain studies. Administration of low doses of pentobarbital significantly decreased PAG spontaneous firing and evoked excitatory and inhibitory PAG neuronal responses. These results suggest that the use of barbiturates to study PAG neuronal responses might have resulted in significant un-intended modifications of the fundamental properties of PAG neuron, as compared to the unanesthetized state. The PAG is important part of pain modulatory network, but the electrophysiological characteristics of PAG neurons in chronic neuropathic pain conditions are still unclear. This issue was addressed by administering a standard chronic pain protocol, using the cancer chemotherapeutic drug, paclitaxel, (2 mg/kg i.p. for 4 alternate days) which induced chronic neuropathic pain, Ten days after treatment, mean spontaneous firing rates of PAG neurons were increased significantly after paclitaxel treatment compared to the pre-paclitaxel treatment levels. PAG neurons in the neuropathic state exhibited significantly increased excitatory neuronal responses to non-noxious stimulus, similar to noxious thermal stimulation and significantly increased excitatory-like neuronal responses as compared to pre-treatment levels. Gabapentin is an anticonvulsant that acts on N type voltage sensitive calcium channels and possesses analgesic properties in chronic pain syndromes. Gabapentin did not significantly affect PAG neuronal responses to acute pain in my initial studies However, gabapentin did produce significant changes in spontaneous and thermal stimuli evoked PAG neuronal firing in paclitaxel-treated rats. Gabapentin induced significant dose-dependent decreases in the elevated spontaneous and evoked PAG neuronal firing to both non-noxious and noxious thermal stimuli in the paclitaxel model of neuropathic pain. I also investigated effects of AM404 on spontaneous and thermal stimuli evoked PAG neuronal firing in paclitaxel-treated rats, I observed that AM404 dose-dependently inhibited elevated spontaneous and evoked PAG neuronal firing in paclitaxel-treated rats. These effects were blocked by pre-treatment with CB1 receptor antagonist (AM251) suggesting a crucial role of CB1 receptor in AM404 mediated analgesic effects. These findings suggest that paclitaxel treatment could lead to plasticity in the PAG that might contribute to generation and maintenance of neuropathic pain. These findings provide the evidence that targeting endogenous cannabinoid system or inhibiting presynaptic calcium channels may be effective in treating neuropathic pain, in part, by actions on the PAG.

Thesis (B.A.)--Haverford College, Dept. of Psychology, 2004. / Includes bibliographical references.

Thesis(MHlthSc(OccTh))--University of South Australia, 1998

Thesis (M. App. Psych.)--University of Adelaide, 1990. / Includes bibliographical references (leaves 108-123).

Thesis (Ph. D.)--University of Wisconsin--Madison. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Washington, 2002. / Vita. Includes bibliographical references (leaves 163-175).

Thesis (M.A.)--York University, 2004. Graduate Programme in Kinesiology and Health Science. / Typescript. Includes bibliographical references (leaves 85-101). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url%5Fver=Z39.88-2004&res%5Fdat=xri:pqdiss&rft%5Fval%5Ffmt=info:ofi/fmt:kev:mtx:dissertation&rft%5Fdat=xri:pqdiss:MQ99325

Thesis (MPsych(Clin))--University of South Australia, 1999

An understanding of pain presupposes that the sufferer is able to use a language which is understood by all. Pain is always described in the language of experience and this experience, encountered by all, is nevertheless lived alone. The interpretive process provides the framework for this study which explores the experiences of five persistent pain sufferers. They have not had their pain validated by diagnosis and persistent pain has become the centrepiece of their existence. The use of epiphany moments illuminates an understanding of the essence of persistent pain experiences, and sufferers are provided with a voice to tell their own stories as their experiences unfold through events in time. These stories are then deconstructed and analysed in order to bring meaning to the lives described. This study found that the communal folklore of pain remains underpinned by dominant ideological forces and discursive practices which sustain the powerlessness of persistent pain sufferers. The sufferer is rendered powerless through medical technologies including the medical interview. Through language the perception of pain is understood and translated in such a way as to cause the sufferer to question the validity of their experience while accepting blame for the persistence of their pain and the need to have it stop. It was postulated that resistance to this process provides the mechanism through which persistent pain sufferers are able to surrender previously held notions of self to alternate identities, which encapsulate the embodied experience of pain. The sufferer can then move to a position where their persistent pain experience is validated. / Doctor of Philosophy (PhD)

Thesis advisor: June Horowitz / Pain in extremely low gestational age (ELGA) infants remains under-assessed and poorly managed despite the fact that pain may have profound consequences with regard to infants' neuro-development (Als, 1982). Pain prevention is a critical goal of pain assessment, yet barriers exist. Most critical is the lack of valid, reliable, and clinically useful pain tools. This observational descriptive study focused on the development of a gestational age appropriate instrument for 24-29 6/7 week infants and evaluation of the new instrument, Pain Assessment and Care for the Extremely Low Gestational Age Infant Focused Instrument (PACEFI). Additionally, differences in behavioral cues and physiologic indicators were evaluated for ELGA infants and very low gestational age (VLGA) infants for non-invasive and invasive procedures. Nurse raters used the PACEFI to rate these infants during both procedures at baseline, during, and recovery to assess variation in expected pain. The PACEFI demonstrated a high internal consistency (.879) and appeared to be contributing to the measurement of pain. A RANOVA found a significant difference in rating scores ( p < .001) for both procedures. Baseline and recovery scores were lower than during scores. ELGA infants demonstrated a dampened response (p < .023) as compared to the VLGA infants during the invasive procedure. Alternatively, ELGA infants demonstrated a more vigorous response for non-invasive procedure and dropped below baseline scores at recovery. The whole care experience during the non-invasive procedure may have led to sensitization for the VLGA infant and overwhelming energy expenditure for the ELGA infant. Furthermore, physiologic indicators and behavioral cues were inconsistent arguing for independent assessment of these parameters. Knowledge gained from this study: 1) provides information regarding gestational age differences in pain behaviors; and (2) clarifies if the measurement of these behaviors addresses the immediate need for pain assessment for this vulnerable population. / Thesis (PhD) — Boston College, 2012. / Submitted to: Boston College. Connell School of Nursing. / Discipline: Nursing.