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. 2010 Oct 13;30(41):13699-706.
doi: 10.1523/JNEUROSCI.2867-10.2010.

Attenuation of activity in an endogenous analgesia circuit by ongoing pain in the rat

Luiz F Ferrari  1 , Robert W Gear, Jon D Levine
Affiliations

Attenuation of activity in an endogenous analgesia circuit by ongoing pain in the rat

Luiz F Ferrari et al. J Neurosci. .

Abstract

Analgesic efficacy varies depending on the pain syndrome being treated. One reason for this may be a differential effect of individual pain syndromes on the function of the endogenous pain control circuits at which these drugs act to produce analgesia. To test this hypothesis, we examined the effects of diverse (i.e., ongoing inflammatory, neuropathic, or chronic widespread) pain syndromes on analgesia induced by activation of an opioid-mediated, noxious stimulus-induced endogenous pain control circuit. This circuit was activated by subdermal capsaicin injection at a site remote from the site of nociceptive testing. Analgesia was not affected by carrageenan-induced inflammatory pain or the early phase of oxaliplatin neuropathy (a complication of cancer chemotherapy). However, the duration of analgesia was markedly shorter in the late phase of oxaliplatin neuropathy and in alcoholic neuropathy. A model of fibromyalgia syndrome produced by chronic unpredictable stress and proinflammatory cytokines also shortened analgesia duration, but so did the same stress alone. Therefore, since chronic pain can activate neuroendocrine stress axes, we tested whether they are involved in the attenuation of analgesic duration induced by these pain syndromes. Rats in which the sympathoadrenal axis was ablated by adrenal medullectomy showed normal duration pain-induced analgesia in groups with either late-phase oxaliplatin neuropathy, alcoholic neuropathy, or exposure to sound stress. These results support the suggestion that pain syndromes can modulate activity in endogenous pain control circuits and that this effect is sympathoadrenal dependent.

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Figures

Figure 1.
Figure 1.
Analgesic effect of capsaicin in naive control rats. The analgesic responses measured in the hindpaw in control rats produced by either capsaicin or vehicle injected subdermally in the forepaw were significantly different. Rats that received capsaicin showed significantly elevated paw-withdrawal thresholds (i.e., analgesia); n = 8 for the group that received capsaicin, and n = 4 for the vehicle group. In this and subsequent figures (except Fig. 2), data are presented as the difference in force in grams from baseline at which withdrawal occurred and are plotted as group mean ± SEM at each time point; PWT, Paw-withdrawal threshold.
Figure 2.
Figure 2.
Paw-withdrawal threshold in pain models. Pain models were induced as follows: intradermal carrageenan injection (1% in a volume of 5 μl), intravenous oxaliplatin administration (2 mg/kg, early-phase and late-phase groups), and alcoholic diet; controls received no prior treatment. Responses were not significantly different among the pain models, but all models demonstrated significant mechanical hyperalgesia compared to control animals; n = 4 for all groups.
Figure 3.
Figure 3.
Effect of carrageenan-induced inflammatory pain on capsaicin-induced analgesia. The analgesic responses of the control and carrageenan (carrag)-pretreated groups to capsaicin (cap) were not significantly different, suggesting that local carrageenan-induced inflammatory hyperalgesia does not affect capsaicin-induced analgesia; n = 8 for the carrageenan/capsaicin group. Data for the control group are replotted from Figure 1, and data for the carrageenan/vehicle (veh) group are replotted from Figure 2 to allow comparison.
Figure 4.
Figure 4.
Effect of chronic widespread pain on capsaicin-induced analgesia. All groups of rats except controls experienced chronic unpredictable sound stress (see Materials and Methods) 14 d before testing. On the day of testing, 2.5 h before the experiment stressed rats received intradermal injections of either PGE2 or its vehicle on the dorsum of the hindpaw. A, PGE2. As expected, the pre-capsaicin baseline for both groups that received PGE2 was lower than the control group (data not shown). Paw-withdrawal thresholds (PWT) remained low for the group that received capsaicin vehicle, but the group that received capsaicin showed early antinociception that lasted only to the 30 min time point, indicating antagonism of capsaicin-induced analgesia duration; n = 6 for both sound stress groups. Data from control group are replotted from Figure 1 for comparison. B, No PGE2 pretreatment. Adrenal-intact rats showed short duration analgesia with a time course similar to that of the rats who received PGE2 (A), indicating that antagonism of capsaicin-induced analgesia was not due to PGE2 administration. This effect was abolished in ADMX rats, suggesting that the shortened analgesic duration is mediated by the sympathoadrenal axis.
Figure 5.
Figure 5.
Effect of alcoholic neuropathy on capsaicin-induced analgesia. The responses of the control and the nonadrenal medullectomized alcohol (EtOH)-pretreated groups to capsaicin were significantly different at the 45 and 60 min time points, indicating that alcohol neuropathy shortens the duration of capsaicin-induced analgesia. This effect was abolished in adrenal medullectomized rats, suggesting that activation of the sympathoadrenal stress axis antagonizes capsaicin-induced analgesia; n = 8 for the EtOH/capsaicin group and the EtOH/capsaicin/ADMX group. Data for the control group are replotted from Figure 1, and data for the EtOH/vehicle group are replotted from Figure 2 to allow comparison. PWT, Paw-withdrawal threshold.
Figure 6.
Figure 6.
Effect of early- and late-phase oxaliplatin-induced neuropathy on capsaicin-induced analgesia. A single dose of oxaliplatin (oxal) was administered intravenously. Testing was performed in separate groups of rats either 2 d (“Early Phase”) or 15 d (“Late Phase”) after oxaliplatin administration. A, Early phase. The responses of the control and the intact and ADMX oxaliplatin-pretreated groups to capsaicin (cap) were not significantly different, indicating that early-phase oxaliplatin neuropathy does not affect capsaicin-induced analgesia; n = 8 for both the oxaliplatin/capsaicin and the ADMX/oxaliplatin/capsaicin groups. Data for the control group are replotted from Figure 2, and data for the oxaliplatin/vehicle (veh) group are replotted from Figure 1 to allow comparison. B, Capsaicin-induced analgesia was significantly shortened in the late-phase intact oxaliplatin group but not the adrenal medullectomized oxaliplatin group, suggesting that late-phase oxaliplatin neuropathy antagonizes capsaicin-induced analgesia and that this effect is mediated by the sympathoadrenal axis; n = 12 for the oxaliplatin/capsaicin group; n = 10 for the ADMX/oxaliplatin/capsaicin group. Data for the control group are replotted from Figure 1, and data for the oxaliplatin/vehicle group are replotted from Figure 2 to allow comparison.
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References

    1. Aley KO, Messing RO, Mochly-Rosen D, Levine JD. Chronic hypersensitivity for inflammatory nociceptor sensitization mediated by the epsilon isozyme of protein kinase C. J Neurosci. 2000;20:4680–4685. - PMC - PubMed
    1. Argoff CE. Clinical implications of opioid pharmacogenetics. Clin J Pain. 2010;26(Suppl 10):S16–S20. - PubMed
    1. Backonja M, Rowbotham MC. Pharmacological therapy for neuropathic pain. In: McMahon SB, Koltzenburg M, editors. Wall and Melzack's Textbook of Pain. 5th Ed. Philadelphia: Elsevier/Churchill Livingstone; 2006. pp. 1075–1083.
    1. Cersosimo RJ. Oxaliplatin-associated neuropathy: a review. Ann Pharmacother. 2005;39:128–135. - PubMed
    1. Dawson J, Sedgwick AD, Edwards JC, Lees P. A comparative study of the cellular, exudative and histological responses to carrageenan, dextran and zymosan in the mouse. Int J Tissue React. 1991;13:171–185. - PubMed

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