Substance P and analgesia

Stewart, John M.; Getto, Carl J.; Neldner, Kenneth H.; Reeve, E. B.; Krivoy, William A.; Zimmermann, E.

doi:10.1038/262784a0

Cited by 197 publications

(61 citation statements)

References 11 publications

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“…It has long been proposed that substance P contributes to nociceptive signaling within the spinal cord dorsal horn, where it is released by nociceptive primary afferent fibers and excites superficial NK1 receptor-expressing projection neurons (Morris et al, 2004). Conversely, supraspinal administration of substance P produces analgesia (Stewart et al, 1976;Frederickson et al, 1978;Malick and Goldstein, 1978;Mohrland and Gebhart, 1979;Improta and Broccardo, 2000). Indeed, behavioral studies of NK1 receptorknock-out mice indicate that these receptors are critical for the full expression of several supraspinally mediated phenomena, including stress-induced analgesia and diffuse noxious inhibitory controls (De Felipe et al, 1998;Bester et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

“…The PAG is a major site of the analgesic actions of -opioids and cannabinoids and forms part of a descending analgesic pathway that projects via the rostral ventromedial medulla (RVM) to modulate nociceptive transmission within the spinal cord dorsal horn (Fields et al, 2006). Microinjection studies in rodents have shown that substance P produces potent analgesia when administered directly into the PAG (Stewart et al, 1976;Frederickson et al, 1978;Malick and Goldstein, 1978;Mohrland and Gebhart, 1979;Rosén et al, 2004). Furthermore, substance P is released within the PAG in response to noxious peripheral stimulation (Xin et al, 1997) and behavioral stress (Rosén et al, 1992), suggesting that endogenous substance P may contribute to PAG-mediated descending analgesia.…”

Section: Introductionmentioning

confidence: 99%

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Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

Drew¹,

Lau²,

Vaughan³

2009

J. Neurosci.

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Substance P is thought to play an essential role in several forms of supraspinally mediated analgesia. The actions of substance P on synaptic transmission within descending analgesic pathways, however, are largely unknown. Here, we used whole-cell recordings from rat midbrain slices to examine the effects of substance P on GABAergic and glutamatergic transmission within the periaqueductal gray (PAG), a key component of a descending analgesic pathway that projects via the rostral ventromedial medulla (RVM) to the spinal cord dorsal horn. We found that substance P reversibly decreased the amplitude and increased the paired-pulse ratio of evoked IPSCs recorded from identified PAG-RVM projection neurons and from unidentified PAG neurons. Substance P had no effect on miniature IPSCs, implying an indirect mode of action. The effects of substance P were abolished by metabotropic glutamate type 5 and cannabinoid CB1 receptor antagonists, but unaltered by NMDA, GABA B , ,␦-opioid, adenosine A 1 , and 5HT 1A receptor antagonists. Consistent with a role for endogenous glutamate in this process, substance P increased the frequency of action potential-dependent spontaneous EPSCs. Moreover, the effect of substance P on evoked IPSCs was mimicked and occluded by a glutamate transport inhibitor. Finally, these effects were dependent on postsynaptic G-protein activation and diacylglycerol lipase activity, suggesting the requirement for retrograde signaling by the endocannabinoid 2-arachidonoylglycerol. Thus, substance P may facilitate descending analgesia in part by enhancing glutamate-mediated excitation and endocannabinoid-mediated disinhibition of PAG-RVM projection neurons.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

Drew¹,

Lau²,

Vaughan³

2009

J. Neurosci.

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“…Synthetic substance P was observed to potentiate LSD-induced tremor in mice (Stern, 1973). Whereas crude substance P has been reported to antagonize morphine analgesia, recent experiments involving intracerebra] and intraperitoneal injection of the synthetic peptide in mice suggested that substance P was capable of causing analgesia of a similar nature to that produced by morphine (Stewart et al, 1976). Furthermore, synthetic substance P abolished the abstinence syndrome in morphinized mice (Stern and Hadzovic, 1973).…”

Section: Interactions Between Substance P and Centrally Acting Drugsmentioning

confidence: 95%

“…Some years earlier it was reported that the administration of substance P to mice increased brain concentrations of serotonin and dopamine but had no effect on acetylcholine, histamine or noradrenaline concentrations (Stern, Hadzovic and Casparovic, 1966;Stern, 1969). With the exception of the experiments by Stewart et al (1976) cited above, the peripheral administration of synthetic substance P in these studies employed enormous doses, viz. up to 500 mg/kg (Stern and Hadzovic, 1973;Stern et al, 1974).…”

Section: Interactions Between Substance P and Centrally Acting Drugsmentioning

confidence: 99%

“…Intracutaneous injections of relatively impure substance P and its application to an exposed blister base produced a burning sensation (Armstrong et al, 1954;Bisset and Lewis, 1962;Jaques, 1963). Recently, however, Stewart et al (1976) found that synthetic substance P was not algogenic on application to the human blister base and suggested that the algogenicity attributed to substance P in crude preparations was due to kinin contamination. A pseudo-affective response was induced in dogs by intra-arterial but not intravenous injections of substance P (Potter et al, 1962).…”

Section: Effects On Afferent Nervesmentioning

confidence: 99%

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Substance P: Its Pharmacology and Physiological Roles

Bury

Mashford

1977

Aust J Exp Biol Med

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Summary. The recent identification and synthesis of the endecapeptide substance P has renewed interest in this naturally occurring compound. The original substance P of Euler and Gadduni was a mixture of biologically active substances, some of which were peptides. The peptide component was responsible for gut-contracting, hypotensive and sialogogic properties attributed to substance P. For almost 40 years following its discovery, substance P resisted isolation and purification. Even the most highly active preparations were heterogeneous and there was a divergence of results from experiments using preparations which were partially purified by different techniques. Nevertheless, much of the early work on the distribution and pharmacology of crude substance P has been confirmed using the synthetic endecapeptide and has stimulated research towards the elucidation of a possible functional role for substance P. Most proposed functions have been highly speculative but, at present, evidence is accumulating in support of a physiological role for substance P as a neurotransniitter in sensory pathways. DISCOVERY, PURIFICATION AND ISOLATION OF SUBSTANCE P.While investigating the distribution of acetylcholine in various tissues in 1931, Euler and Caddum detected the presence of a substance in alcoholic extracts of equine brain and intestine which stimulated contraction of isolated rabbit intestine. On intravenous administration to anaesthetized rabbits, this preparation briefly lowered the blood pressure. These effects differed qualitatively from those of acetylcholine and, in addition, were not inhibited by atropine. The active moiety found in the dried extracts was given the working designation "preparation P" and was shown to differ in its chemical and biological properties from other smooth muscle stimulating substances then known, viz. histamine and the adenine nucleotides. The new active factor, provisionally named substance P (Caddum and Schild, 1934), was first recognised as a protein-like material by Euler (1936a).

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Immunocytochemical localization of substance P receptor in rat periaqueductal gray matter: A light and electron microscopic study

Barbaresi

1998

J. Comp. Neurol.

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The distribution of substance P receptor (SPR) protein in the rat periaqueductal gray matter (PAG) was investigated with a polyclonal antibody in the four subdivisions obtained by cytochrome-oxidase histochemistry (Co-hi). At light microscopic analysis, immunoreactivity appeared particularly dense in the dorsal subdivision of the PAG, was less intense in the other subdivisions, and formed several longitudinally organized columns. SPR-like immunoreactivity (SP(R-i)) was localized mostly to cell bodies and dendrites of small and medium-sized neurons, which constituted about 6% of the total neuronal population of the PAG. At the electron microscopic level, SP(R-i) could be observed on postsynaptic as well as on nonsynaptic regions of both cell bodies and dendrites. A small proportion of axons (4.2%) and axon terminals (5.3%) showed SP(R-i), the majority of labeled axon terminals, amounting to about 70% of synapsing elements, formed asymmetric synapses with dendrites. Rare astroglial processes displaying SP(R-i) were also observed scattered throughout the neuropil of all PAG subdivisions. Our observations suggest that 1) also in the PAG, SP may act in a diffuse, nonsynaptic manner, probably on targets that are distant from its sites of release; and 2) SP may modulate excitatory neurotransmission acting presynaptically on those labeled axons that form asymmetric synapses.

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Substance P and analgesia

Cited by 197 publications

References 11 publications

Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

Substance P Drives Endocannabinoid-Mediated Disinhibition in a Midbrain Descending Analgesic Pathway

Substance P: Its Pharmacology and Physiological Roles

Immunocytochemical localization of substance P receptor in rat periaqueductal gray matter: A light and electron microscopic study

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