Mechanisms of reduced opioid effectiveness in a rat model of neuropathic pain

摘要

Peripheral nerve injury can result in long-lasting, abnormal pain states referred to as neuropathic pains. These pains can result in increased sensitivity to both noxious (hyperalgesia) and non-noxious stimuli (allodynia) and are often characterized as resistant to alleviation by opioids. Neuropathies are accompanied by various neuropathological changes, including: (1) alterations in spinal neurotransmitter levels (including cholecystokinin (CCK), enkephalin and dynorphin); (2) degeneration of primary afferents; (3) formation of ectopic foci and dorsal horn sensitization; (4) abnormal sympathetic innervation and (5) sprouting of Abeta fibers to form novel synapses. The hypotheses of this dissertation are (1) information of an allodynic nature is transmitted by Abeta fibers, which do not contain opioid receptors, therefore only the post-synaptic pool of receptors is available for opioid interaction, resulting in a loss of opioid efficacy; (2) the maintenance of the neuropathic pain state is mediated by tonic activity at excitatory amino acid receptors (possibly by dynorphin) which may contribute to the loss of opioid effectiveness; and (3) increases in spinal CCK attenuate opioid effectiveness by inhibition of the activity of endogenous enkephalins. The initial hypothesis is supported by results showing that low efficacy opioids (morphine and SNC 80) are ineffective at alleviating nerve injury-induced allodynia while high efficacy opioids (DAMGO, (D-Ala2 Glu4) deltorphin and biphalin) produced a significant antiallodynic action. This strengthens the suggestion that a reduced opioid receptor pool exists for the treatment of allodynia. Additionally, selective destruction of C-fibers by capsaicin alters responses to thermal but not mechanical stimuli. These results suggests that allodynia from nerve injury is mediated by Abeta fibers, which do not possess opioid receptors. The second hypothesis is supported by the result that MK 801 and dynorphin A (1-13) antisera restore the effectiveness of morphine suggesting that increased dynorphin levels affect opioid efficacy, possibly through an NMDA mediated mechanism. Finally, blockade of CCKB receptors can also enhance the efficacy of opioids in a naltrindole reversible fashion, suggesting that CCKB blockade may increase morphine's effectiveness by increasing the availability of an endogenous delta-opioid, possibly (Leu-5) enkephalin. These findings may lead to a better understanding of the role of opioids in neuropathic pain and the development of better treatments for these conditions.