The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline.
Noradrenaline (NA), a key neurotransmitter of the endogenous pain inhibitory system, acutely inhibits nociceptive transmission (including that mediated by substance P), potentiates opioid analgesia, and underlies part of the antinociceptive effects of the widely prescribed tricyclic antidepressants. Lesions of noradrenergic neurons, however, result in either normal or reduced pain behavior and variable changes in morphine antinociception, undermining the proposed association between noradrenaline (NA) deficiency and chronic pain (hyperalgesia). We used mice lacking the gene coding for dopamine beta-hydroxylase, the enzyme responsible for synthesis of NA from dopamine, to reexamine the consequences of a lack of NA on pain behavior. Here, we show that absence of NA in the central nervous system results in a substance P-mediated chronic hyperalgesia (decreased nociceptive threshold) to thermal, but not mechanical, stimuli and decreased efficacy of morphine. Contrary to studies that show substance P-mediated hyperalgesia requires intense stimuli, we found that even a mild stimulus is sufficient to evoke substance P-dependent hyperalgesia in the NA-deficient mice. Restoring central NA normalized both the nociceptive threshold and morphine efficacy, which is consistent with a tonic inhibitory effect of NA on nociceptive transmission. Unexpectedly, however, antagonists to the substance P receptor (the NK1 receptor) could achieve the same effect as NA replacement. We conclude that when unopposed by NA, substance P acting at the NK1 receptor causes chronic thermal hyperalgesia, and that the reduced opioid efficacy associated with a lack of NA is due to increased NK1-receptor stimulation.
Jasmin
Luc
L
Department of Neurological Surgery, University of California, San Francisco, CA 94143-0112, USA. ucpain@itsa.ucsf.edu
Tien
Duc
D
Weinshenker
David
D
Palmiter
Richard D
RD
Green
Paul G
PG
Janni
Gabriella
G
Ohara
Peter T
PT
D000818:Animals; D001933:Brain Stem / Q000033:anatomy & histology / Q000502:physiology; D004299:Dopamine beta-Hydroxylase / Q000172:deficiency / Q000235:genetics; D004351:Drug Resistance; D006358:Hot Temperature; D006930:Hyperalgesia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D064729:Neurokinin-1 Receptor Antagonists; D009638:Norepinephrine / Q000172:deficiency* / Q000502:physiology; D017288:Pain Threshold / Q000187:drug effects / Q000502:physiology; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology; D018040:Receptors, Neurokinin-1 / Q000502:physiology*
D064729:Neurokinin-1 Receptor Antagonists; D018341:Receptors, Adrenergic, alpha-2; D018040:Receptors, Neurokinin-1; D009020:Morphine; D004299:Dopamine beta-Hydroxylase; D009638:Norepinephrine