Role of μ-opioid and NMDA receptors in the development and maintenance of repeated swim stress-induced thermal hyperalgesia

Section of Pharmacology, Instituto de Investigaciones Clínicas, Facultad de Medicina, University of Zulia, Apartado Postal 1151, Maracaibo 4001-A, Venezuela.
Behavioural Brain Research (Impact Factor: 3.03). 03/2006; 167(2):205-11. DOI: 10.1016/j.bbr.2005.09.006
Source: PubMed


Repeated exposure to swimming stress induces a long-lasting hyperalgesia in the rat by mechanisms to be elucidated. Since opioid and glutamate neurotransmitter systems modulate pain, we now evaluated the effect of pharmacological blockade of opioid and glutamate receptors subtypes on forced swimming stress-induced hyperalgesia. Male rats were daily subjected to 10-20 min of forced or sham swimming for 3 days and thermal nociception was estimated twice, before each behavioral conditioning and 24 h after the last, using hot plate test. Selective opioid and NMDA receptor antagonists were administered i.p. either before each conditioning session or before the second nociception assessment. Unlike sham swimming rats, forced swimming rats showed significant reductions in hot plate response latencies (hyperalgesia) after the last swimming session, as compared to pre-stress values. Rats treated with the opioid receptor antagonists naloxone (0.1 mg/kg, non-subtype-selective) and naloxonazine (5 mg/kg, mu(1)-subtype-selective), before each forced swimming, did not become hyperalgesic, whereas those treated before the second post-stress assessment of nociception developed hyperalgesia. Naltrindole (0.5 mg/kg, delta-subtype-selective) and nor-binaltorphimine (0.5mg/kg, kappa-subtype-selective) were inactive in both administration schedules. The efficacy of morphine (3-7.5 mg/kg) to produce analgesia in forced swimming rats was lower than in sham swimming rats. Rats treated with the NMDA antagonist ketamine (5 mg/kg) before the forced swimming or the second post-stress assessment of nociception did not have hyperalgesia. Thus, swim stress-induced hyperalgesia might be initiated by the repeated stimulation of mu-opioid and NMDA receptors but maintained only by the activity of NMDA receptors.

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Available from: Heberto Suarez-Roca, Oct 04, 2015
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    • "null mice but not in their wild-type littermates. Although hyperalgesia following either single or repeated stress has been reported previously and different neurotransmitter/neuropeptide systems have been implicated in this response (Imbe et al., 2006; Khasar et al., 2008; Quintero et al., 2000; Suarez-Roca et al., 2006; Vidal and Jacob, 1982), our results are novel and showing that beta-endorphin is important not only in mediating antinociception elicited by a short swim, but also in preventing the development of a delayed hyperalgesic response. The hyperalgesic response could have been due an imbalance between the nociceptive inhibitory and excitatory mechanisms following repeated hot plate measurements. "
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    ABSTRACT: Stress is known to elicit pain relief, a phenomenon referred to as stress-induced analgesia. Based on stress parameters, opioid and non-opioid intrinsic pain inhibitory systems can be activated. In the present study, we assessed whether changing the duration of stress would affect the involvement of endogenous opioids in antinociception elicited by swim in warm water (32 °C), known to be opioid-mediated. Using mice lacking beta-endorphin, enkephalins or dynorphins and their respective wild-type littermates, we assessed the role of each opioid peptide in antinociception induced by a short (3 min) vs. long (15 min) swim. Mice were tested for baseline hot plate latency, exposed to swim (3 or 15 min) in warm water (32 °C) and then tested for antinociception at 5, 15 and 30 min. Our results revealed that both swim paradigms induced significant antinociception in wild-type mice. However, the short swim failed to induce antinociception in beta-endorphin-deficient mice, illustrating that beta-endorphin is important in this form of stress-induced antinociception. On the other hand, antinociception elicited by the long swim was only slightly reduced in beta-endorphin-deficient mice despite pretreatment with naloxone, a non-selective opioid receptor antagonist, significantly attenuated the antinociception elicited by the long swim. Nevertheless, a delayed hyperalgesic response developed in mice lacking beta-endorphin following exposure to either swim paradigm. On the other hand, mice lacking enkephalins or dynorphins and their respective wild-type littermates expressed a comparable antinociceptive response and did not exhibit the delayed hyperalgesic response. Together, our results suggest that the endogenous opioid peptide beta-endorphin not only mediates antinociception induced by the short swim but also prevents the delayed hyperalgesic response elicited by either swim paradigm.
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