Research reportOpioid and non-opioid NMDA-mediated predator-induced analgesia in mice and the effects of parasitic infection
Introduction
Evidence exists for the presence of multiple endogenous pain inhibitory systems that can be activated by environmental stressors. Both naloxone-reversible `opioid' and naloxone-insensitive `non-opioid' forms of stress-induced analgesia (SIA) have been indicated with the nature of the SIA depending on the parameters of the stressor, i.e. intensity, duration 37, 38. Analgesia is an important component of the responses to stimuli associated with real or potential danger 5, 15and both opioid and non-opioid mediated analgesia are evident in rodents exposed to predator cues 16, 17, 18, 24, 25. Analgesia would be adaptive in these threatening situations, reducing responses to distracting stimuli and facilitating the performance of various active (e.g. fleeing) and passive (e.g. immobility) defensive behaviours.
The expression of non-opioid analgesia has been associated with a number of neurochemical systems, including the γ-aminobutyric A (GABAA) receptor component of the GABA-benzodiazepine system, the N-methyl-d-aspartate (NMDA) receptor of the excitatory amino acid, glutamate-system and serotonergic (5-HT) systems 2, 4, 16, 17, 33, 34. Not all of the aforementioned neuromodulatory systems, however, have been considered in relation to the analgesia arising from ethologically meaningful aversive situations, such as predator exposure. In particular, examinations of the roles of NMDA systems in the mediation of non-opioid SIA have, to date, been largely restricted to the specific laboratory stressors of forced swim 21, 27, 28.
It has further become evident that a variety of other biological factors (e.g. age, sex and reproductive status, species, strain and population, behavioral and physiological status) are able to affect the display of SIA (e.g. 21, 27, 28). One highly important, but often neglected, biological factor is parasitic infection. There is growing evidence that parasites affect host behavior in a variety of ways other than the obvious pathologic and immunological changes 29, 30. Results of diverse studies have revealed alterations in various behaviors in parasitized animals that may either directly or indirectly increase their vulnerability to predation (e.g. 13, 14, 22, 26, 36). In particular, male laboratory mice subclinically infected with the natural, single host, enteric, protozoan parasite, Eimeria vermiformis, showed a diminished analgesic response to the presence of a predatory cat 18, 19. However, interpretations of these responses were confounded by the opioid analgesia induced by the acute E. vermiformis infection itself.
The murine trichostrongylid nematode, Heligmosomoides polygyrus, is a well-known parasite used in elucidating host–parasite relationships 1, 35. Eggs of this parasite are shed in the feces of infected hosts and free living stages develop in the environment and are infective to other mice that acquire them during feeding and grooming [12]. At low, subclinical and non-pathological levels, H. polygyrus has a number of behavioral effects in mice, including reductions in social dominance and spatial learning performance 10, 20.
In the present study we consider: (1) the roles of opioid and non-opioid systems in the mediation of predator odor-induced analgesia; and (2) the effects of a subclinical infection with H. polygyrus on predator-induced analgesia. We describe the effects of brief (30 s) and a more prolonged (15 min) duration of exposure to the major component of weasel, Mustela erminea, odor (2-propylthietane) 6, 7and control odor (butyric acid) on the nociceptive responses of mice infected with H. polygyrus and uninfected mice. In addition, we describe the effects of the prototypic opiate antagonist, naloxone, the 5-HT1A agonist, 8-hydroxy-2-(din-n-propylamino)tetralin (8-OH-DPAT) [8], the GABAA antagonist, bicuculline, and the competitive NMDA antagonist, NPC 12626 (2-amino-4,5-(1,2 cyclohexyl)-7-phospoheptanoic acid) 9, 39, on the predator-induced nociceptive responses of infected and uninfected mice.
Section snippets
Animals
Male mice (CF-1 strain derived) 2–3 months of age (25–30 g), were housed singly in clear polyethylene cages with wood shavings and ground corn cob bedding at 20±2°C under a 12:12 h light/dark cycle (light 08.00–20.00 h). Food (Mouse Breeder Blox, Wayne Laboratory Animal Diets, Madison, WI) and water were available ad libitum. Infected and uninfected mice were housed in separate rooms.
Parasite infection
Mice were infected by oral intubation with H. polygyrus larvae under light Metofane (Pitman–Moore, Toronto,
Thirty-second exposure
Uninfected mice exposed to the odor of a predator showed increased thermal latencies, indicative of the induction of analgesia, as compared with uninfected mice exposed to either the control odor or no odor condition. However, the responses latencies of the infected mice following exposure to the predator odor did not differ from those of the infected mice exposed to either the control odor or no odor (odor×treatment, F2,24=16.64, P<0.001; Fig. 2A). Thus, the presence of the parasitic infection
Discussion
These results show that: (1) exposure to the odor of a predator, the weasel, induced marked opioid and non-opioid, NMDA-mediated, analgesic responses in male laboratory mice; and (2) subclinical parasitic infection eliminated the non-opioid and significantly reduced the opioid mediated, predator-induced analgesia.
These findings demonstrate that exposure to the odor of a natural predator induced significant opioid- and non-opioid-mediated analgesic responses in male laboratory mice, with the
Acknowledgements
We thank Dr. M.E. Scott for supplying the H. polygyrus, Phero-Tech Inc. for providing the 2-propylthietane and Nova Pharmaceuticals for the NPC 12626. We thank Terry Seely, Joan Ingoldsby, Dawn Gray and Christine Himsl-Rayner for their assistance, and Dr. K.-P. Ossenkopp for statistical advice. This research was supported by Agriculture and Agri-Food Canada and the Natural Sciences and Engineering Research Council of Canada.
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