Regulation of morphine antiallodynic efficacy by cholecystokinin in a model of neuropathic pain in rats

Neuropathic pains have often been classified as opioid-resistant. Here, spinal (intrathecal) actions of morphine and nonmorphine opioids have been studied in a nerve ligation model of neuropathic pain in rats. Mechanical allodynia was evaluated using von Frey filaments. Nerve-injured animals exhibited allodynia that was stable for up to 6 weeks after the surgery. Morphine did not alter allodynia at doses up to 300 nmol (100 μg). In contrast, [D-Ala², NMPhe⁴, Gly-ol]enkephalin (DAMGO), a high-efficacy μ opioid agonist, produced a significant, dose-related antiallodynic action. [D-Ala², Glu⁴]deltorphin (δ agonist) produced a significant antiallodynic effect only at 300 nmol, reaching approximately 70% of the maximum. Coadministration of morphine with a dose of [D-Ala², Glu⁴]deltorphin, which was inactive alone, produced a significant and long-lasting antiallodynic action that was antagonized by NTI (δ receptor antagonist); NTI alone had no effect. Although blockade of cholecystokinin-B (CCK(B)) receptors with L365,260 did not produce effects alone, a significant antiallodynic action was observed when coadministered with morphine; this elevation of nociceptive threshold was abolished by NTI. The finding that DAMGO, but not very large doses of morphine, produced antiallodynic actions suggests that the ability of μ opioids to alleviate the allodynia is related, in part, to efficacy at postsynaptic μ receptors. At an inactive dose, a δ agonist or a CCK(B) antagonist enhanced morphine antiallodynic efficacy in an NTI-sensitive fashion. CCK(B) receptor blockade may enhance endogenous enkephalin actions, resulting in enhancement of morphine efficacy through a μ-δ receptor interaction. Mechanistically, it is suggested that the failure of morphine, but not DAMGO, to produce antiallodynic effects in this model is related, in part, to the requirement for sufficient efficacy to modulate transmission of impulses strictly through postsynaptic sites. Additionally, the upregulation of anti-μ substances (e.g., CCK) seem to limit observed efficacy of morphine. The data imply that treatment of disorders related to neuropathies may require use of high-efficacy μ opioids, or high doses of lower-efficacy opioids, and suggest the possibility that δ agonists and antagonists at CCK(B) receptors may be useful adjuncts for the treatment of such conditions.