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7 Cards in this Set
- Front
- Back
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Provide a brief history of opium and its derivatives.
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Source - opium poppy, Papaver somniferum
Origin - Asia Minor Name - from the Greek ‘opion’ (poppy juice) Effects - pain relief, euphoria, narcosis 6000y (Sumerians) TO EUROPE: Via Arabic influences on Western medicine use widespread in Europe by mid-C16 included in many patent medicines e.g. ‘laudanum’ - Paracelsus PROBLEMS & REFINEMENT Variation in purity of opium led to variation in its effects, from analgesia to death Dosing precision aided by: 1803 - Serturner isolates active ingredient and names it morphine (after Morpheus, the Greek God of dreams) late C19 - invention of syringe & hypodermic needle DOUBLE-EDGED PROGRESS medical progress paralleled by growth in opiate abuse Medical concern: opium smoking, opium ‘eating’, patent medicines, US Civil War Public concern: Opium Wars, popular writings e.g. Thomas de Quincey 25% raw opium made up of alkaloids of these, morphine accounts for 40% remaining 60% = c.20 other compounds most relevant codeine - mild analgesic (action?) papa |
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Discuss role played by addiction in opiate research.
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CHRONIC EFFECTS:
tolerance shift to the right in dose-response curve variations in tolerance cross-tolerance dependence ‘withdrawal’ or ‘abstinence’ syndrome symptoms opposite those of acute opiate effects rarely fatal PRIMARY ABSTINENCE SYNDROME: begins within a few hours of discontinuation agitation, yawning, insomnia glandular hyperactivity -‘cold turkey’ severe stomach cramps involuntary muscle spasms -‘kicking the habit’ compulsive drug craving severity gradually declines over days RELAPSE: secondary abstinence lasts weeks after main physical symptoms disappear state of physical/psychological unease conditioned abstinence lasts long after primary/secondary abstinence occasioned by cues previously associated with environment in which drugs sought/taken (associative learning) Both cases: user awareness of ‘cure’ JANUS-LIKE PROFILE opiates have desirable (pain relief) and undesirable (dependence) effects research goal to produce non-addictive analgesics biochemical modific |
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Outline evidence (indirect and direct) for opiate receptors and endogenous opioids.
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One way to explain powerful effects of opiates is to postulate existence of specific receptors
Beckett & Casey (1954): indirect evidence effects seen at low doses phenomenon of cross-tolerance similarity of molecular structure stereospecifity small structural change = opiate antagonists l-isomers active mirror-image d-isomers (not shown) inactive DIRECT EVIDENCE! discovery of opiate binding sits in brain Radioligand binding 1971 - Avram GOLDSTEIN (Palo Alto) disappointing results (<2% specific) 1973 - Solomon SNYDER (Baltimore) Lars TERENIUS (Uppsala) Eric SIMON (New York) all 3 groups reported 80+% specific binding: difference lay in affinity of the radioligand employed Although possible that binding sites were a mere artefact:- binding was found to be stereospecific high correlations found between affinity & effect inhibition of smooth muscle contractions clinical efficacy as analgesics binding sites therefore true ‘receptors’ LOCALISATION: found in all vertebrates & |
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Explain adaptive value of pain.
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PAIN PATHWAYS:
Neo: conveys sharp fast pain Paleo: conveys dull slow pain Opiate receptors dense in paleospinothalamic system, & opiate drugs clinically useful only in dull aching pain opiate receptors could not have evolved to interact with plant-derived or synthetic opiates endogenous morphine-like factor must exist? skepticism fostered by early failures to detect one key finding ensured survival of the ‘endogenous opiate’ hypothesis stimulation-produced analgesia David Reynolds (1969) - electrical stimulation of brain produces profound analgesia (SPA) key region - periaqueductal gray matter (PAG) of the midbrain Huda Akil et al (1974) - SPA prevented by opiate antagonist, naloxone implication? stimulation endogenous opiate release in PAG, analgesia via opiate receptors in this region FIRST ENDOGENOUS "opiates" DISCOVERED: 1975-6 Hughes & Kosterlitz (Aberdeen)* Terenius (Uppsala) Snyder (Baltimore) * elegantly simple approach used to identify endogenous opiates in |
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Summarize Gate Control theory of pain.
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pain is adaptive pain is multidimensional & variable Gate Control Theory Postulated a ‘gating’ mechanism in the spinal cord that determines whether or not pain messages are sent to brain Gate is controlled not only by competing sensory inputs but also by descending mechanisms |
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Describe research demonstrating existence of intrinsic pain inhibitory systems.
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PAG rich in opiate receptors/opioid peptides
Stimulation-produced analgesia is reversed by naloxone [Reynolds 1969; Akil et al 1974] Direct application of morphine in PAG also produces analgesia that is naloxone-reversible [Yaksh et al 1976] Lesions to descending pathways from PAG to spinal cord block both forms of analgesia [Basbaum & Fields 1979] Q: a powerful intrinsic analgesia system exists centered on the midbrain PAG, but why? A: to inhibit pain - not good enough! the key question concerns the circumstances under which the system is normally engaged ironically, first clue came with demonstration that system can be triggered by pain itself Akil et al (1976) - footshock induces naloxone-reversible analgesia in rats confirmed by many labs who also reported analgesia in response to diverse stressors (most non-painful) But not all found to involve opioid substrates Cannon et al (1982): 2 regions of PAG, dorsal & ventral stimulation of ventral PAG - opioid analgesia stimulation of dorsal PAG - non- |
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Consider in detail research on the adaptive significance of pain inhibition for living organisms.
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"STRESS" ANALGESIA
Akil et al (1976) - footshock induces naloxone-reversible analgesia in rats confirmed by many labs who also reported analgesia in response to diverse stressors (most non-painful) But not all found to involve opioid substrates Cannon et al (1982): 2 regions of PAG, dorsal & ventral stimulation of ventral PAG - opioid analgesia stimulation of dorsal PAG - non-opioid analgesia 2 pain inhibitory systems opioid & non-opioid Electrical stimulation of both dPAG and vPAG produces analgesia Only the analgesia from vPAG is blocked by naloxone Watkins & Mayer (1982,1986) Terman et al (1984) Rodgers & Randall (1988) Butler & Finn (2009) focus: underlying mechanisms as revealed by pharmacology, biochemistry & endocrinology identify at least 4 intrinsic analgesia systems doubly-dissociated on two dimensions neural vs endocrine mechanisms opioid vs non-opioid mechanisms Liebeskind et al. (1976) ‘Analgesia may be an adaptive response to dire circumstances, enabling the organism to defensiv |
