Approximately two-thirds of patients will experience pain following spinal cord injury (SCI). This pain can arise as an immediate consequence of SCI, or can develop over time into chronic, neuropathic pain. Individuals are frequently prescribed opioid analgesics, including morphine, for the treatment of pain in both the acute and chronic phases of SCI. Yet, despite the prevalence of opioid use, no studies have examined the addictive potential of opioids, or their secondary effects, following spinal injury. These experiments used a clinically relevant self-administration paradigm to examine both addiction and functional recovery after morphine administration. To assess morphine administration in the acute phase of SCI, animals were placed in operant chambers 24-hours following spinal injury. In the chambers, depression of a reinforced lever resulted in an intravenous infusion of morphine (or vehicle). Animals were placed in the chambers for 7, 12-hour sessions and could administer up to 30 mg of morphine per session. Morphine self-administration was also examined in the chronic phase of injury. Animals were placed into operant chambers for 7, 12-hour sessions beginning 14 or 35 days after injury. The amount of morphine administered, as well as recovery of locomotor function and general health, was compared across subjects with SCI and sham (no injury) controls. In the acute phase of injury, SCI significantly reduced self-administration of morphine, but administration led to decreased recovery of locomotor function and weight loss. In the chronic phase of injury, self-administration did not differ between contused and sham animals. All subjects administered the full amount of morphine available each day. In this phase of injury, morphine administration led to significant weight loss, but did not attenuate recovery of locomotor function. These studies suggest that spinal injury reduced the addictive potential of morphine in the acute, but not the chronic, phase of SCI. However, acute administration of high doses of morphine decreased recovery of locomotor function. Morphine should not be used in this phase of injury for the clinical treatment of pain. In the chronic phase, opioid use must be closely monitored as use may result in addictive behavior.

The present study used the conditioned place preference (CPP) paradigm to examine the neural mechanisms underlying morphine's rewarding effect in the rat. Of thirteen sites tested with intra-cerebral morphine injections, only the ventral tegmental area (VTA) and periaqueductal gray (PAG) produced a CPP, suggesting that morphine's rewarding effect is initiated by an action at these sites. The CPPs induced by intra-VTA and intra-PAG morphine may be produced by different mechanisms because animals conditioned with these two injections exhibited different patterns of behaviour during testing. Injections of a quaternary opioid antagonist into either the VTA or PAG blocked a CPP to systemic morphine, confirming that opiate-induced reward is mediated via opioid receptors in these sites. Lesions of the pedunculopontine tegmental nucleus (PPT$ rm sb{g}),$ ventral striatum (VS), PAG, or fornix reduced a CPP to morphine, although PAG and fornix lesioned animals displayed a CPP when tested in a drugged state. These findings suggest that PPT$ rm sb{g}$ and VS lesions reduce the rewarding effect of morphine, and that PAG and fornix lesions disrupt the ability to retrieve information about the relationship between conditioned and unconditioned stimuli.

Recently we have begun to investigate a novel role of EphB receptors in opiate-dependant analgesia. EphB2-β-galactosidase knockins demonstrate that EphB2 is persistently expressed within a number of neural pathways involved in MOR-mediated nociception in vivo and that EphB2 colocalizes with markers of the MOR at the cellular level in the spinal cord and dorsal root ganglia. Despite demonstrating wild-type levels of sensory and motor activity, EphB2 null mice exhibit a significantly altered analgesic response to repeated (but not naive) opiate exposure compared to controls. Investigation of EphB2 null mice and wild type animals revealed no differences in MOR protein levels or affinity. Analysis of this opiate-mediated tolerance suggests that associative phenomena play a substantial role in mediating the analgesic effects observed, possibly due to defeciencies in CA1-mediated learning. Therefore, loss of EphB2 may diminish context-dependent learning and that such learning plays a substantial role in regulating morphine-dependent tolerance.

There has been a great deal of research investigating drug combinations which can increase analgesia. A number of studies have been conducted with one particular combination--opioids combined with the amphetamine drugs. Despite the existing literature, this combination is rarely used in clinical practice. One purpose of this thesis is to review the literature pertaining to the opioid-amphetamine combination. Another purpose of this thesis is to investigate whether dextroamphetamine sulfate ($ circler$Dexedrine) can potentiate morphine sulfate analgesia in rats in the formalin test (Experiment 1). To investigate whether these results can be generalized to another psychostimulant, methylphenidate hydrochloride ($ circler$Ritalin) is used in Experiment 2. Methylphenidate has been chosen instead of another amphetamine drug because it is currently being used in clinical studies without supporting evidence from animal studies. The results of the two experiments indicate that low doses of d-amphetamine and methylphenidate can potentiate the analgesic effects of morphine.

Thesis (Ph. D.)--University of Hawaii at Manoa, 1991. / Includes bibliographical references (leaves 41-43, 244-250) / Microfiche. / xiii, 374 leaves, bound ill. 29 cm

Thesis (PhD)--University of South Australia, 2001.

Thesis (MAppSc in Pharmacy)--University of South Australia, 1996

Thesis (MAppSc) -- University of South Australia, 1998

No description available.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 5 uppsatser.