The NK1 receptor mediates both the hyperalgesia and the resistance to morphine in mice lacking noradrenaline

Abstract

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 ␤-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. N oradrenaline (NA) is an essential neurotransmitter of the endogenous pain inhibitory system (1, 2) that tonically and phasically inhibits spinal nociceptive transmission, including that mediated by substance P (3, 4). By stimulating central nervous system (CNS) ␣ 2 adrenoreceptors, NA increases threshold and latency to noxious stimuli without affecting responses to innocuous stimuli, and potentiates the antinociceptive effects of opiates (5-10).Based on the above understanding, it has been suggested that noradrenergic dysfunction is a key component of certain chronic intractable pain disorders (11). A major caveat is that this hypothesis is based primarily on experimental studies that use acute rather than chronic pain. Although acute lesions or inhibition of noradrenergic spinal afferents produce a state of hyperalgesia and reduced antinociceptive effects of opiates (2, 10, 12), the increased pain behavior abates over time. In fact, long-term effects of noradrenergic denervation have been reported to result in decreased pain behavior, whereas the antinociceptive effect of morphine is either reduced, unchanged, or increased (13-17). These conflicting results can be caused in part by the variability in the extent of the removal of noradrenergic neurons or terminals which, when using a neurotoxin, is both incomplete and nonselective. Moreov...

There and Back Again: A Tale of Norepinephrine and Drug Addiction

“…NE has also been implicated in diverse central processes and diseases, including learning and memory, neuronal excitability, pain, and affective disorders (Ressler and Nemeroff, 1999;Gibbs and Summers, 2002;Jasmin et al, 2002;Weinshenker et al, 2001;Murchison et al, 2004). The brain noradrenergic system is comprised of two main ascending projections: the dorsal noradrenergic bundle (DNB), which originates in the A6 locus coeruleus (LC) and projects to the hippocampus, cerebellum, and forebrain, and the ventral noradrenergic bundle (VNB), which arises in a number of nuclei of the pons and medulla, such as the A1 and A2 cell groups, and innervates the hypothalamus, midbrain, and extended amygdala (reviewed by Moore and Bloom, 1979).…”

Haplotype architecture of the norepinephrine transporter gene SLC6A2 in four populations

“…In humans, norepinephrine (NE) is essential to fundamental cognitive and emotional processes including attention, learning and memory, perception of emotions, and perception of pain (Foote et al 1983;Jasmin et al 2002). NE is also involved in autonomic control via its actions in the brainstem and as the primary neurotransmitter at postganglionic sympathetic nerve terminals (Hahn et al 2003).…”

Substance P, opioid, and catecholamine systems in the mouse central nervous system (CNS)

“…I n an article in this issue of PNAS, Jasmin et al (1) provide new evidence that noradrenaline is a key neurotransmitter in the endogenous pain inhibitory systems in the central nervous system (CNS) of the mouse. They show that this adrenergic inhibitory system interacts with that part of the sensory nociceptive system by using the neuropeptide substance P in a mutually antagonistic manner.…”

“…This variability fits with current ideas on the plastic nature of pain but underlines the need for new animal models in which chronic pain states can be studied. Accordingly, to avoid the problems that plagued earlier studies, Jasmin et al (1) chose to do experiments in mice in which the gene for dopamine-␤-hydroxylase (DBH, the enzyme that converts dopamine to noradrenaline) had been genetically deleted (8). These mice can have their normal noradrenergic function restored by the ingenious expedient of dosing them with L-threo-3,4-dihydroxyphenylserine (DOPS), a synthetic amino acid precursor of noradrenaline that can be converted to noradrenaline by aromatic amino acid decarboxylase (AADC, which is present in both control and DBH Ϫ͞Ϫ mice).…”

“…CNS noradrenergic neurons and their projections were preserved in DBH knockout mice, thereby providing the circuitry from which noradrenaline could be released once its synthesis was established by giving DOPS͞carbidopa. As Jasmin et al (1) believed that part of the antinociceptive effect of ␣ 2 -adrenoreceptor stimulation might be the result of the inhibition of substance P release from primary afferent fibers, they studied the effects of drugs that blocked the action of substance P at its target NK 1 receptors on the thermal hyperalgesia seen in DBH knockout mice. All three antagonists used (RP-67580, CP-96345, and L-733060) reversed the hyperalgesia in the knockout mice but not in control mice, and inactive enantiomers of two of these blockers were without effect, confirming that the responses studied were indeed operated through NK 1 receptors.…”