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

Abstract

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. They conclude that substance P, when unopposed by tonic release of noradrenaline, is the major factor underlying thermal hyperalgesia. Jasmin et al. also present evidence that the reduced opioid efficacy seen in the absence of noradrenaline is the result of increased NK 1 receptor stimulation by endogenous substance P. Their paper (1) is a good example of the way in which critical, and well controlled, experiments on transgenic animals can help to elucidate complex problems in neurobiology. This fascinating study supports other recently published work suggesting that substance P has a key role in pain perception in the mouse by way of critical interactions with other systems, e.g., the PAR2 proteasedependent receptor (2, 3).It has been accepted for many years that noradrenaline is a key neurotransmitter in the descending inhibitory systems by which the brainstem controls the sensitivity of the dorsal horn of the spinal cord to nociceptive sensory inputs (4). Synaptically released noradrenaline acts through ␣ 2 adrenoceptors to reduce the sensitivity of dorsal horn relay neurons to noxious but not to nonnoxious stimuli and it also potentiates the effects of opioid drugs, such as morphine (5, 6). Investigations using agonist and antagonist drugs to examine interactions between effects mediated by opioid receptors and adrenoceptors have sometimes given confusing results, as have studies where pathways have been lesioned or chemically depleted of their transmitter content. It has thus been difficult to investigate the putative noradrenergic dysfunction believed to underlie some chronic pain conditions in humans (7). 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). A further refinement is that, if the mice are dosed with carbidopa, an AADC inhibitor which does not cross the bloodbrain barrier, and then given DOPS, it is possible to replace the brain noradrenaline in the DBH knockout mice, leaving peripheral noradrenaline absent (9). The DB...

Effects of the NK1 antagonist, aprepitant, on response to oral and intranasal oxycodone in prescription opioid abusers

“…2006), affective dysfunction (including anxiety and depression) (Santarelli et al . 2002; Herpfer & Lieb 2005; Ebner & Singewald 2006) and pain perception (Hill 2002; King et al . 2005; Trang et al .…”

Action of tachykinins in the rat hippocampus: modulation of inhibitory synaptic transmission

“…Tachykinin NK1 receptors present in the central nervous system appear to be involved in several regulatory functions (Quartara & Maggi, 1998; Rupniak & Kramer, 1999; Saria, 1999; Hill, 2002). NK1 receptors in brainstem neurons play a role in pain transmission, cardiovascular and respiratory regulation and emesis, whereas NK1 receptors present in neurons located in the amygdala or related brain areas probably play a role in anxiety and depression.…”