An antagonist of substance P N-terminal fragments, d-substance P(1–7), reveals that both nociceptive and antinociceptive effects are induced by substance P N-terminal activity during noxious chemical stimulation

Substance P (SP) N-terminal fragments are known to alter nociception when injected intrathecally or when released in response to capsaicin. However, it is not known whether a sufficient concentration of SP N-terminal metabolites accumulate during noxious stimulation to modulate nociception. To test this, we examined the effect of the SP(1–7) antagonist, d-SP(1–7), injected intrathecally in mice, on two nociceptive assays that are differentially affected by exogenous SP(1–7): acetic acid-induced writhing that is inhibited and formalin-induced behaviors that are enhanced by SP(1–7). One nmol of d-SP(1–7) is sufficient to block the acute (30 min) antinociceptive effects of SP(1–7) on writhing. When injected alone at much higher doses (10–100 nmol), d-SP(1–7) inhibited writhing. In the formalin assay, SP(1–7) had no acute effect (30 min) on responses during Phase 1 at any dose tested, but d-SP(1–7) increased responses 5 min after injection of low (2–1000 pmol), but not high doses (10 and 100 nmol). Twenty-four hours after injection of SP(1–7), writhing was inhibited and formalin responses were increased. d-SP(1–7) prevented these effects of SP(1–7) but had no effect when injected alone, indicating that there is no tonic SP N-terminal activity in mice not exposed to noxious stimuli. Thus, acetic acid and formalin each induce endogenous SP N-terminal activity, respectively, producing a pro-nociceptive effect that is relatively insensitive to d-SP(1–7) and antinociception that is very sensitive to inhibition by d-SP(1–7).     

Simultaneous multisite recordings of neural ensemble responses in the motor cortex of behaving rats to peripheral noxious heat and chemical stimuli

Chronic motor cortex (MCx) stimulation (MCS) is an effective approach for patients with chronic, intractable neuropathic pain. However, the underlying neural mechanisms are less known. Combining an in vivo simultaneous multisite recording technique with a video-based behavioral tracker, simultaneous neuronal ensemble activities of the MCx and behavioral responses to noxious heat stimuli applied to bilateral hindpaw pads under naïve and inflammatory pain state were studied in freely behaving rats receiving prior implantation of microwire multielectrode array (2 × 4). Totally, 81 active units were sorted and separated from 40 microwire electrodes pre-implanted in the MCx of 5 rats. Under naïve state, 41% (33/81) units were responsive to contralateral, while 27% (22/81) were responsive to ipsilateral heat stimuli. However, the proportion of heat-responsive units under inflammatory pain state induced by subcutaneous bee venom (BV) injection was significantly increased when compared with saline control (BV vs. saline: 60% vs. 48% for contralateral and 51% vs. 37% for ipsilateral, P < 0.05, n = 81 units) as a consequence of recruitment of some previously heat non-responsive to heat sensitive units. Moreover, under the BV-inflamed condition, the discharge rate of the MCx neurons was significantly increased. The time course of increased spontaneous neuronal ensemble activities (n = 81) was in parallel with that of pain-related behaviors following BV injection. It is concluded that there are pain-related neurons in the MCx that can be functionally changed by peripheral inflammatory pain condition.     

Effects of polyclonal and monoclonal antibodies to substance P on slow excitatory transmission in rat spinal dorsal horn

The effects of bath perfusion of polyclonal and monoclonal antibodies to substance P (SP) on slow excitatory transmission in rat dorsal horn have been investigated by intracellular recording in the immature rat spinal cord slice preparation. Both polyclonal and monoclonal antibodies to SP produced a significant decrease in the amplitude and the duration of the slow depolarization generated in dorsal horn neurons by high intensity, repetitive dorsal root stimulation or exogenous SP application. The effect of endogenous SP, or SP-related peptide, released during dorsal root stimulation appears likely since bath perfusion of a slice with a normal rabbit serum, or affinity chromatography preadsorbed SP antiserum, or non-specific IgG, or 5-hydroxytryptamine antiserum had no similar depressant effect. These results, if taken together with other experimental evidence, suggest that SP, or SP-like peptide, is in some way involved in a generation of the dorsal root-evoked slow depolarization. In addition, a novel approach is presented for using polyclonal and monoclonal antibodies to SP as pharmacological antagonists. Use of a specific characterized monoclonal antibody for the detection of physiological and pharmacological effects of putative peptide transmitters in vitro opens new avenues for further investigations.     

Transient changes in P2X3 but not TRPV1 mRNA expression in rat after prenatal exposure to glucocorticoids

TRPV(1) and P2X(3) receptors are cation channels known to modulate responses to noxious stimuli. In the nervous system, these receptors are preferentially expressed in the pathways that transmit pain signal from the periphery to the brain. The aim of this study is to determine whether prenatal exposure to glucocorticoids alters the expression of P2X(3) and TRPV(1) in the dorsal root ganglia (DRG) and spinal cord (SC) during early postnatal development. Time-pregnant rats received daily subcutaneous injection of dexamethasone (100 microg/kg/day) or a vehicle from prenatal days 9 to 20. The DRG and lumbar/sacral SC of the newborn rats were harvested on postnatal days 1, 7, and 42 for a quantitative real-time PCR analysis of messenger RNAs. In the control rats, mRNA level of P2X(3) and TRPV(1) receptors from DRG remained relatively constant from postnatal days 1 to 42 while those from SC were significantly higher on postnatal day 42 than days 1 and 7. Prenatal treatment with dexamethasone significantly decreased P2X(3) receptor mRNA level in the DRG and SC on postnatal day 1. Such an effect was no longer statistically significant on postnatal day 7, and disappeared completely on postnatal day 42. Expression of TRPV 1 was not altered by dexamethasone regardless of anatomical localization or developmental stages. Therefore, prenatal exposure to glucocorticoids leads to a transient inhibition of P2X(3) expression in the DRG and SC, suggesting a potential involvement of P2X(3) receptors in the unique profile of pain perception in neonates.     

Altered host response to murine gammaherpesvirus 68 infection in mice lacking the tachykinin 1 gene and the receptor for substance P

The tachykinins are implicated in neurogenic inflammation and the neuropeptide substance P in particular has been shown to be a proinflammatory mediator. A role for the tachykinins in host response to viral infection has been previously demonstrated using either TAC1- or NK1 receptor-deficient transgenic mice. However, due to redundancy in the peptide-receptor complexes we wished determine whether a deficiency in TAC1 and NK1^R in combination exhibited an enhanced phenotype. TAC1 and NK1^R-deficient mice were therefore crossed to generate transgenic mice in both (NK1^−/− × TAC1^−/−). As expected, after infection with the respiratory pathogen murine gammaherpesvirus (MHV-68), TAC1 and NK1^R-deficient mice were more susceptible to infection than wild-type C57BL/6 controls. However, unexpectedly, NK1^−/− × TAC1^−/− mice were more resistant to infection arguing for a lack of feedback inhibition through alternative receptors in these mice. Histopathological examination did not show any great differences in the inflammatory responses between groups of infected animals, except for the presence of focal perivascular B cell accumulations in lungs of all the knockout mice. These were most pronounced in the NK1^−/− × TAC1^−/− mice. These results confirm an important role for TAC1 and NK1^R in the control of viral infection but reinforce the complex nature of the peptide-receptor interactions.     

Latencies of the P300 component of the auditory event-related potential in depression are related to the Bech-Rafaelsen Melancholia Scale but not to the Hamilton Rating Scale for Depression

The relationship between severity of depression and the P300 latency of auditory event-related potential was investigated in 36 patients with a major depressive episode according to DSM-III. Positive correlations were found between of the P300 latency and the total score of the Bech-Rafaelsen Melancholia Scale (BRMS), the 4 retardation items of the BRMS (motor, verbal, intellectual and emotional) and the item for lowered mood. In contrast, latencies were not associated with the scores of the Hamilton Rating Scale for Depression, which considers retardation to a lesser extent than the BRMS.