Abstract
We have previously shown that the balance of electrically evoked descending brainstem control of spinal nociceptive reflexes undergoes a switch from excitation to inhibition in preadolescent rats. Here we show that the same developmental switch occurs when μ-opioid receptor agonists are microinjected into the rostroventral medulla (RVM). Microinjections of the μ-opioid receptor agonist [D-Ala2, N-MePhe4, Gly-ol]-enkephalin (DAMGO) into the RVM of lightly anaesthetised adult rats produced a dose-dependent decrease in mechanical nociceptive hindlimb reflex electromyographic activity. However, in preadolescent (postnatal day 21 [P21]) rats, the same doses of DAMGO produced reflex facilitation. RVM microinjection of δ-opioid receptor or GABAA receptor agonists, on the other hand, caused reflex depression at both ages. The μ-opioid receptor-mediated descending facilitation is tonically active in naive preadolescent rats, as microinjection of the μ-opioid receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP) into the RVM at this age decreases spinal nociceptive reflexes while having no effect in adults. To test whether tonic opioid central activity is required for the preadolescent switch in RVM descending control, naloxone hydrochloride was delivered continuously from subcutaneous osmotic mini-pumps for 7-day periods, at various postnatal stages. Blockade of tonic opioidergic activity from P21 to P28, but not at earlier or later ages, prevented the normal development of descending RVM inhibitory control of spinal nociceptive reflexes. Enhancing opioidergic activity with chronic morphine over P7 to P14 accelerated this development. These results show that descending facilitation of spinal nociception in young animals is mediated by μ-opioid receptor pathways in the RVM. Furthermore, the developmental transition from RVM descending facilitation to inhibition of pain is determined by activity in central opioid networks at a critical period of periadolescence.
Highlights
Pain modulatory networks in the brain play an active role in controlling spinal nociceptive responses so that pain perception is influenced by our state of arousal, attention and expectation
This supraspinal pain modulation is mediated by networks distributed throughout the limbic system and midbrain which exert their control at the level of the dorsal horn of the spinal cord, via antiand pro-nociceptive descending pathways arising in the rostral ventral medulla (RVM) [4,5,6,10]
The gate control theory of pain of Melzack and Wall [27] was the first clear articulation of the central role of these descending pathways in processing noxious sensory information, and since it has become clear that endogenous supraspinal mechanisms exert powerful control over spinal cord pain circuits mediating such phenomena as placebo analgesia [10] and playing a key role in the maintenance of chronic pain states [29]
Summary
Pain modulatory networks in the brain play an active role in controlling spinal nociceptive responses so that pain perception is influenced by our state of arousal, attention and expectation. Because RVM networks are pronociceptive before P21, microinjection of l-opioid receptor agonists into the RVM of young animals activates descending control of nociceptive reflexes, but that the effect is facilitatory. We hypothesise that opioid networks have a trophic role in the maturation of supraspinal pain control and that the transition from descending facilitation to inhibition in the preadolescent period is dependent upon endogenous opioid signalling in the immature brain. Using electromyography (EMG) recordings in response to noxious mechanical stimulation, we show that spinal excitability is differentially modulated by intra-RVM microinjection of the l-opioid receptor agonist DAMGO in preadolescent and adult rats. We further identify a critical period when this tonic endogenous opioid activity determines the normal maturation of supraspinal pain control
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