SYSTEMATIC STUDY OF SELECTIVE SPINAL ANALGESIA

点击翻译按钮获取中文摘要

DESCRIPTION: (Adapted from the applicant's abstract) In the past grant cycle, the investigators have completed preclinical toxicity screening for intrathecal (IT) neostigmine and demonstrated dermatomally restricted, dose dependent analgesia in humans, which correlated significantly with CSF neostigmine concentration. IT neostigmine increases acetylcholine in human CSF, and studies in rats demonstrate a muscarinic mechanism of action for neostigmine induced analgesia. IT neostigmine also potentates analgesia from intraspinal a2-adrenergic agonists in humans and rats. In this proposal, the investigators will turn from cholinesterase inhibition to monamine reuptake inhibition, using amitriptyline. IT amitriptyline causes no behavioral analgesia to acute noxious stimulation in rats, but synergistically enhances analgesia from IV morphine. This would be expected if systemic opioids activate bulbospinal inhibitory aminergic pathways. In addition to monoamine reuptake inhibition, amitriptyline is a functional NMDA antagonist in vitro, and the investigators preliminary data suggest that IT amitriptyline is antinociceptive, similar to other NMDA antagonists, in a variety of animal models of hyperalgesia and allodynia. This proposal will complete preclinical toxicity testing and safety assessment of IT amitriptyline and test its effect on acute nociceptive pain alone, its interaction with IV alfentanil in acute nociceptive pain, and its efficacy alone against intradermal capsaicin induced hyperalgesia and allodynia in humans. These effects will be correlated with CSF neurotransmitter and amitriptyline concentrations to provide presumptive evidence for mechanisms in humans. In addition, the pharmacological mechanisms of IT amitriptyline in nociceptive and hyperalgesic pain will be assessed in detail in rats.