Research reportAntinociception following opioid stimulation of the basolateral amygdala is expressed through the periaqueductal gray and rostral ventromedial medulla
Introduction
The mammalian nervous system contains neural circuits which, when activated by environmental stressors or direct stimulation, are able to modulate the ascending transmission of noxious information. A large number of studies conducted over the last 25 years have focused on the role of the midbrain periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) in pain modulation. Opioid sensitive cells located in the ventrolateral PAG project to RVM neurons which in turn are capable of inhibiting noxious input at the level of the dorsal horn of the spinal cord [2]and animals with lesions of the PAG or RVM fail to show normal inhibition of nociceptive reflexes when exposed to certain environmental stressors 11, 35.
Recent work has shown that in behaving animals the expression of changes in nociception in response to stress often depends on neurons within the amygdala. Lesions of the amygdala prevent the hypoalgesia that is normally seen in rats exposed to a signal for foot shock 14, 12. Similar lesions also affect the ability of systemically administered opioid agonists like morphine to produce antinociception [22]. Chemical stimulation of the amygdala will often result in changes in pain sensitivity. Injections of several neuropeptide receptor agonists and other compounds in the rat amygdala have been shown to affect nociception in rats 1, 13, 15, 17, 24. We have recently shown that application of μ opioid receptor agonists to the basolateral region (BLA) of the amygdala will result in robust inhibition of the radiant heat tail flick (TF) reflex in barbiturate anesthetized animals 10, 13.
Antinociception produced by direct manipulation of the amygdala or by exposure to environmental stress may result from the activation of a neural circuit which includes the amygdala, PAG, and RVM. The central nucleus of the amygdala (CeA) shares dense reciprocal projections with the PAG [31], lesions of the amygdala or PAG produce very similar patterns of behavioral results [16], and injection of opioid agonists in the amygdala affects the release of opioid peptides in the PAG as well as other brain structures 20, 21. One recent electrophysiological study has shown that a large number of PAG cells respond to both chemical and electrical stimulation of the CeA and that a portion of these evoked responses may be dependent on the release of endogenous opioid peptides within the PAG [6].
In the present study we evaluate the idea that inhibition of the TF reflex following microinjection of μ opioid receptor agonists in the BLA is expressed via a descending circuit which includes the ventrolateral PAG and RVM by making electrolytic lesions or microinjecting lidocaine into brainstem sites following opioid injections in the amygdala. Antinociception on the TF test is usually defined as an increase in the latency to emit a suprathreshold motor response following application of radiant heat to the skin of the animal's tail. However, recent work has shown that descending control of this reflex may be expressed through changes in response amplitude as well as latency 3, 4. Accordingly an additional aim of this study was to compare measures of TF amplitude and latency to determine if these parameters would be differentially affected by stimulation of the amygdala or manipulation of the PAG or RVM. Finally, since the amygdala, PAG, and RVM each appear to be involved in the regulation of several behavioral and autonomic functions in addition to nociception (e.g., Refs. 11, 18, 19, 32, 34), we also monitored cardiovascular activity during these experiments.
Section snippets
Subjects
A total of 44 Long Evans male rats (350 g–500 g) obtained from Harlan Sprague Dawley (Madison, WI) were used as subjects. Animals were housed in hanging stainless steel cages and allowed free access to rat chow and water. The vivarium was maintained on a 14:10 h light/dark cycle. All testing was conducted during the light portion of the cycle.
Surgical preparation
All animals were initially anesthetized prior to TF testing with an IP injection of sodium pentobarbital (50 mg ml−1 kg−1). A catheter constructed from
PAG lidocaine
Fig. 1 depicts the distribution of injection sites in the BLA for rats treated with LID or SAL in the PAG. Only animals with injection sites located bilaterally in the basolateral region of the amygdala (including the basolateral and lateral nulcei, after de Olmos et al., [5]) were included in the statistical analysis. Four rats in the LID pretreatment group were excluded from the analysis because at least one of the two forebrain injection sites was located outside of the BLA. As reported
General discussion
The results of the present study, when taken together with previous work using awake animals, support our contention that spinal nociceptive reflexes may be modulated through a descending circuit which includes the amygdala, PAG, and RVM. The involvement of μ opioid receptors in the amygdala as well as in the PAG [33]and RVM 7, 8, 26may reflect general organizational principles related to antinociception at the neural systems level and the amygdala may represent the rostral extension of a chain
Acknowledgements
This work was supported by grants from the National Institute on Drug Abuse (DA09429) and the National Institute of Mental Health (MH49819) to FJH. We are grateful to G. Gale for expert technical assistance.
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Cited by (0)
- 1
Present address: Department of Neurology, College of Medicine, University of California – San Francisco, CA, USA.
- 2
Present address: Department of Neurology, Medical College of Wisconsin.