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. 2010 Nov 24;171(1):344-50.
doi: 10.1016/j.neuroscience.2010.08.035. Epub 2010 Aug 22.

Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat

E K Joseph  1 , J D Levine
Affiliations

Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat

E K Joseph et al. Neuroscience. .

Abstract

Sensitization to mechanical stimuli is important in most pain syndromes. We evaluated the populations of nociceptors mediating mechanical hyperalgesia and those mediating mu-opioid receptor (MOR) and delta-opioid receptor (DOR) agonist-induced inhibition of hyperalgesia, in the rat. We found that: (1) intradermal injection of both the endogenous ligand for the Ret receptor, glia-derived growth factor (GDNF), and the ligand for the tropomyosin receptor kinase A (TrkA) receptor, nerve growth factor (NGF)-which are present on distinct populations of nociceptors-both produce mechanical hyperalgesia; (2) DOR agonist 4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazin-1-yl](3-methoxyphenyl)methyl]-N,N-diethylbenzamide (SNC) but not MOR agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) inhibit GDNF-induced hyperalgesia; (3) both DAMGO and SNC inhibit NGF hyperalgesia, even in rats pretreated with isolectin B4 (IB4)-saporin, a toxin that destroys IB4-binding neurons; (4) co-administration of low doses of DAMGO and SNC produce enhanced analgesia, and; (5) repeated administration of DAMGO produces cross-tolerance to the analgesic effect of SNC. These findings demonstrate that, most nociceptors have a role in mechanical hyperalgesia, only the DOR agonist inhibits GDNF hyperalgesia, and MOR and DOR are co-localized on a functionally important population of TrkA-positive nociceptors.

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Figures

Figure 1
Figure 1
A Effect of delta and mu-opioid receptor agonists on GDNF and NGF-induced mechanical hyperalgesia Intradermal injections of GDNF (10 ng, n = 8) and NGF (1 µg, n = 8) produced significant (p < 0.001) mechanical hyperalgesia (reduction in the paw withdrawal threshold, measured on the dorsal side of the hind paw of the rat. Administration of SNC (delta-opioid receptor agonist, 100ng, n = 8), prior (15') to GDNF significantly (p < 0.001) attenuated GDNF-induced mechanical hyperalgesia, while DAMGO (mu-opioid receptor agonist, 1 µg, n = 8) failed to attenuate GDNF-induced mechanical hyperalgesia. However, similar treatment with both SNC (100 ng, n =6), and DAMGO (1 µg, n = 8) prior (15’) to NGF resulted in significant attenuation of NGF-induced hyperalgesia. B Effect of intraspinal IB4-Saporin (neurotoxin) treatment Intradermal injection of GDNF (10 ng, n = 6) to rats, previously (10 days prior) treated with IB4-Saporin intraspinally failed to induce mechanical hyperalgesia, while in IB4-Sap treated rats NGF (1 µg, n = 6) still produced robust hyperalgesia, which was significantly (p < 0.001) attenuated by both SNC (100 ng, n = 8) and DAMGO (1 µg, n = 8).
Figure 2
Figure 2. Synergistic attenuating effect
Sub-effective doses of SNC (10ng) and DAMGO (100ng), both administered separately but 15' prior to NGF (1 µg, n = 8) produced synergistic attenuation (p
Figure 3
Figure 3. Cross tolerance with repeated DAMGO treatment
Both SNC (delta-opioid agonist), which significantly attenuated NGF and GDNF–induced hyperalgesia in naïve animals failed to attenuate NGF or GDNF-induced hyperalgesia in repeated DAMGO (1 µg, hourly, 3 times) treated rats (both n = 6). Similarly, DAMGO (mu-opioid agonist), which attenuated NGF-induced hyperalgesia in naïve animals, failed to attenuate NGF-induced hyperalgesia in repeated DAMGO (1 µg, hourly, 3 times) treated rats (n = 4).
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