Attenuation of reflex pressor and ventilatory responses to static contraction by an NK-1 receptor antagonist

1992 ◽  
Vol 73 (4) ◽  
pp. 1389-1395 ◽  
Author(s):  
J. M. Hill ◽  
J. G. Pickar ◽  
M. P. Kaufman
Keyword(s):  
Spinal Cord ◽  
Substance P ◽  
Receptor Antagonist ◽  
Dorsal Horn ◽  
Intrathecal Injection ◽  
Muscular Contraction ◽  
Muscle Afferents ◽  
Neurokinin A ◽  
Ventilatory Responses ◽  
Static Contraction

The chemical messengers released onto second-order dorsal horn neurons from the spinal terminals of contraction-activated group III and IV muscle afferents have not been identified. One candidate is the tachykinin substance P. Related to substance P are two other tachykinins, neurokinin A (NKA) and neurokinin B (NKB), which, like substance P, have been isolated in the dorsal horn of the spinal cord and have receptors there. Whether NKA or NKB plays a transmitter/modulator role in the spinal processing of the exercise pressor reflex is unknown. Therefore, we tested the following hypotheses. After the intrathecal injection of a highly selective NK-1 (substance P) receptor antagonist onto the lumbosacral spinal cord, the reflex pressor and ventilatory responses to static muscular contraction will be attenuated. Likewise, after the intrathecal injection either of an NK-2 (NKA) receptor antagonist or an NK-3 (NKB) receptor antagonist onto the lumbrosacral spinal cord, the reflex pressor and ventilatory responses to static contraction will be attenuated. We found that, 10 min after the intrathecal injection of 100 micrograms of the NK-1 receptor antagonist, the pressor and ventilatory responses to contraction were significantly (P < 0.05) attenuated. Mean arterial pressure was attenuated by 13 +/- 3 mmHg (48%) and minute volume of ventilation by 120 +/- 38 ml/min (34%). The cardiovascular and ventilatory responses to contraction before either 100 micrograms of the NK-2 receptor antagonist or 100 micrograms of the NK-3 receptor antagonist were not different (P > 0.05) from those after the NK-2 or the NK-3 receptor antagonists.(ABSTRACT TRUNCATED AT 250 WORDS)

Attenuation of reflex pressor and ventilatory responses to static muscular contraction by intrathecal opioids

1990 ◽  
Vol 68 (6) ◽  
pp. 2466-2472 ◽  
Author(s):  
J. M. Hill ◽  
M. P. Kaufman
Keyword(s):  
Mean Arterial Pressure ◽  
Arterial Pressure ◽  
Opioid Peptides ◽  
Intrathecal Injection ◽  
Muscular Contraction ◽  
Muscle Afferents ◽  
Triceps Surae ◽  
Reflex Responses ◽  
Ventilatory Responses ◽  
Static Contraction

We have tested the hypothesis that intrathecal injections of opioid peptides attenuate the reflex pressor and ventilatory responses to static contraction of the triceps surae muscles of chloralose-anesthetized cats. We found that before intrathecal injections of [D-Ala2]Met-enkephalinamide (100 micrograms in 0.2 ml), static contraction increased mean arterial pressure and ventilation by 32 +/- 5 (SE) mmHg and 227 +/- 61 (SE) ml/min, whereas after injection of this opioid peptide, static contraction increased mean arterial pressure and ventilation by only 15 +/- 5 mmHg and 37 +/- 33 ml/min, respectively. The attenuation of both the pressor and ventilatory responses to static contraction by [D-Ala2]Met-enkephalinamide were statistically significant (P less than 0.05). Moreover, the attenuation was probably not caused by an opioid-induced withdrawal of sympathetic outflow because [D-Ala2]Met-enkephalinamide had no effect on the pressor and ventilatory responses evoked by high-intensity electrical stimulation of the central cut end of the sciatic nerve. In addition, intrathecal injection of peptides that were highly selective agonists for either the opioid mu- or delta-receptor attenuated the reflex responses to static contraction. Naloxone (1,000 micrograms), injected intrathecally, prevented the attenuation of the reflex responses to contraction by opioid peptides. We speculate that the opioid-induced attenuation of the reflex pressor and ventilatory responses to static contraction may have been due to suppression of substance P release from group III and IV muscle afferents.

Blockade of non-NMDA receptors attenuates reflex pressor response to static contraction

1994 ◽  
Vol 266 (5) ◽  
pp. H1769-H1776 ◽  
Author(s):  
J. M. Hill ◽  
J. G. Pickar ◽  
M. P. Kaufman
Keyword(s):  
Nmda Receptor ◽  
Substance P ◽  
Receptor Antagonist ◽  
Pressor Response ◽  
Intrathecal Injection ◽  
Ventilatory Responses ◽  
Exercise Pressor Reflex ◽  
Static Contraction ◽  
Substance P Receptor ◽  
Pressor Reflex

Considerable evidence suggests that both substance P and glutamate play a role in the spinal transmission of the exercise pressor reflex. We tested two hypotheses. First, after a lumbosacral intrathecal injection of a glutamatergic receptor antagonist, the reflex cardiovascular and ventilatory responses to static contraction are attenuated. Second, after a lumbosacral intrathecal injection of a substance P receptor antagonist and a glutamatergic receptor antagonist, the reflex cardiovascular and ventilatory responses to static contraction are abolished. We found that 1) the reflex cardiovascular responses to static contraction were unaffected (P > 0.05) after the intrathecal injection of the N-methyl-D-aspartate (NMDA) receptor antagonists, dl-2-amino-5-phosphonopentanoate (+/- AP-5) or 3-[(+-)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (+/- CPP); 2) the reflex pressor response to static muscular contraction was attenuated by > 50% after the intrathecal injection of the non-NMDA receptor antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX); and 3) the reflex pressor response to static contraction was almost abolished after the intrathecal injection of the substance P receptor antagonist, CP-96,345, and CNQX. Our results suggest that substance P and glutamate are two neurotransmitters involved in the spinal transmission of the exercise pressor reflex and that substance P and glutamate exert their effects via neurokinin-1 (NK-1) and non-NMDA receptors, respectively.

scholarly journals Glutamatergic receptor dysfunction in spinal cord contributes to the exaggerated exercise pressor reflex in heart failure

2015 ◽  
Vol 308 (5) ◽  
pp. H447-H455 ◽  
Author(s):  
Han-Jun Wang ◽  
Rebecca Cahoon ◽  
Edgar B. Cahoon ◽  
Hong Zheng ◽  
Kaushik P. Patel ◽  
...  
Keyword(s):  
Heart Failure ◽  
Spinal Cord ◽  
Receptor Antagonist ◽  
Dorsal Horn ◽  
Pressor Response ◽  
Glutamate Release ◽  
Exercise Pressor Reflex ◽  
Dorsal Horns ◽  
Static Contraction ◽  
Pressor Reflex

Excitatory amino acids (e.g., glutamate) released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR) in physiological conditions. However, the role of glutamate and glutamate receptors in mediating the exaggerated EPR in the chronic heart failure (CHF) state remains to be determined. In the present study, we performed microinjection of glutamate receptor antagonists into ipisilateral L4/L5 dorsal horns to investigate their effects on the pressor response to static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots in decerebrate sham-operated (sham) and CHF rats. Microinjection of glutamate (10 mM, 100 nl) into the L4 or L5 dorsal horn caused a greater pressor response in CHF rats compared with sham rats. Furthermore, microinjection of either the broad-spectrum glutamate receptor antagonist kynurenate (10 mM, 100 nl) or the N-methyl-d-aspartate (NMDA) receptor antagonist dl-2-amino-5-phosphonovalerate (50 mM, 100 nl) or the non-NMDA-sensitive receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (5 mM, 100 nl) into L4/5 dorsal horns decreased the pressor response to static contraction in CHF rats to a greater extent than in sham rats. Molecular evidence showed that the protein expression of glutamate receptors (both non-NMDA and NMDA) was elevated in the dorsal horn of the lumbar spinal cord in CHF rats. In addition, data from microdialysis experiments demonstrated that although basal glutamate release at the dorsal horn at rest was similar between sham and CHF rats (225 ± 50 vs. 260 ± 63 nM in sham vs. CHF rats, n = 4, P > 0.05), CHF rats exhibit greater glutamate release into the dorsal horn during muscle contraction compared with sham rats (549 ± 60 vs. 980 ± 65 nM in sham vs. CHF rats, n = 4, P < 0.01). These data indicate that the spinal glutamate system contributes to the exaggerated EPR in the CHF state.

Attenuating effects of intrathecal clonidine on the exercise pressor reflex

1991 ◽  
Vol 70 (2) ◽  
pp. 516-522 ◽  
Author(s):  
J. M. Hill ◽  
M. P. Kaufman
Keyword(s):  
Arterial Pressure ◽  
Intrathecal Injection ◽  
Muscular Contraction ◽  
Muscle Afferents ◽  
Ventilatory Responses ◽  
Exercise Pressor Reflex ◽  
Adrenergic Antagonist ◽  
Anesthetic Action ◽  
Intrathecal Clonidine ◽  
Stimulation Of

We tested the hypothesis that intrathecal injection of clonidine, an alpha 2-adrenergic agonist, attenuated the reflex cardiovascular and ventilatory responses to static muscular contraction in cats. Before clonidine (1 microgram in 0.2 ml), contraction-induced reflex increases (n = 10) in mean arterial pressure and ventilation averaged 25 +/- 3 mmHg and 359 +/- 105 ml/min, respectively, whereas after clonidine these increases averaged 8 +/- 4 mmHg and 200 +/- 114 ml/min, respectively (P less than 0.05). Clonidine had no effect on the heart rate response to contraction. Intrathecal injection of yohimbine (10 micrograms; n = 5), an alpha 2-adrenergic antagonist, but not prazosin (10 micrograms; n = 3), an alpha 1-adrenergic antagonist, prevented the attenuating effects of clonidine on the reflex pressor and ventilatory responses to contraction. Our findings were not due to the spread of clonidine to the medulla, because the reflex pressor and ventilatory responses to contraction were not attenuated by injection of clonidine (1 microgram) onto the medulla (n = 3). In addition, our findings were not due to a clonidine-induced withdrawal of sympathetic outflow, because intrathecal injection of clonidine (1 microgram) did not attenuate increases in arterial pressure and ventilation evoked by high-intensity electrical stimulation of the cut central end of the sciatic nerve (n = 5). Furthermore, our findings were not due to a local anesthetic action of clonidine, because application of this agent to the dorsal roots had no effect on the discharge of group IV muscle afferents. We conclude that stimulation of alpha 2-adrenergic receptors in the spinal cord attenuates the reflex pressor and ventilatory responses to static contraction.

scholarly journals The alleviation of neuropathic pain behaviours by a single injection of a synthetic substance P-botulinum conjugate persists for up to 120d and can be restored with a second injection of conjugate.

2020 ◽  
Author(s):  
Maria Maiarù ◽  
Charlotte Leese ◽  
Bazbek Davletov ◽  
Stephen P. Hunt
Keyword(s):  
Spinal Cord ◽  
Neuropathic Pain ◽  
Botulinum Toxin ◽  
Substance P ◽  
Dorsal Horn ◽  
Single Injection ◽  
Intrathecal Injection ◽  
Lumbar Spinal Cord ◽  
Projection Neurons ◽  
Mechanical Hypersensitivity

There is an urgent need for new pain-relieving therapies. We have previously shown using mouse models of persistent pain that a single intrathecal injection of substance P conjugated to the light chain of botulinum toxin (SP-BOT) silenced neurons in the dorsal horn of the spinal cord and alleviated mechanical hypersensitivity. The SP-BOT construct selectively silenced neurokinin 1 receptor positive (NK1R+) neurons in the superficial dorsal horn of the spinal cord. A subset of these NK1R+ neurons are nociceptive projection neurons and convey injury-related information to the brainstem, initiating and maintaining programmes of escape and recovery essential for healing. Previously, we observed a reduction in mechanical hypersensitivity in a spared nerve injury (SNI) model of neuropathic pain state after intrathecal injection of SP-BOT over the lumbar spinal cord and lasting for up to 40 days. In this latest study, we have extended these observations and now show that thermal and affective measures of pain behaviour were also alleviated by a single intrathecal injection of SP-BOT. By introducing SNI 30 days, 60 days, 90 days or 120 days after injection of SP-BOT we have established that NK1R+ spinal neurons in the superficial lamina of the dorsal horn were silenced for up to 120 days following a single intrathecal injection of the botulinum construct. We also show that behavioural alleviation of neuropathic pain symptoms could be reinstated by a second injection of SP-BOT at 120 days. Taken together this research demonstrates that this recently developed botulinum toxin conjugate provides a powerful new way of providing long term pain relief without toxicity following a single injection and also has a therapeutic potential for repeated dosing when pain begins to return.

Distribution of substance P in the spinal cord of patients with syringomyelia

1996 ◽  
Vol 84 (6) ◽  
pp. 992-998 ◽  
Author(s):  
Thomas H. Milhorat ◽  
Harrison T. M. Mu ◽  
Carole C. LaMotte ◽  
Ade T. Milhorat
Keyword(s):  
Spinal Cord ◽  
Substance P ◽  
Dorsal Horn ◽  
Ventral Horn ◽  
Immunohistochemical Method ◽  
Positive Staining ◽  
Content Type ◽  
Normal Individuals ◽  
Neurologically Normal ◽  
Intermediolateral Nucleus

✓ The distribution of substance P, a putative neurotransmitter and pain-related peptide, was studied using the peroxidase—antiperoxidase immunohistochemical method in the spinal cords obtained from autopsy of 10 patients with syringomyelia and 10 age- and sex-matched, neurologically normal individuals. Substance P immunoreactivity was present in axons and in terminal-like processes in close apposition to neurons in the first, second, and third laminae of the dorsal horn. Smaller amounts of peroxidase-positive staining were found in the fifth lamina of the dorsal horn, the intermediolateral nucleus, the intermediomedial nucleus, and the ventral horn. In nine of 10 patients with syringomyelia, there was a substantial increase in substance P immunoreactivity in the first, second, third, and fifth laminae below the level of the lesion. A marked reduction or absence of staining was present in segments of the spinal cord occupied by the syrinx. Central cavities produced bilateral abnormalities, whereas eccentric cavities produced changes that were ipsilateral to the lesion. No alterations in staining were found in the spinal cord of an asymptomatic patient with a small central syrinx. The authors conclude that syringomyelia can be associated with abnormalities in spinal cord levels of substance P, which may affect the modulation and perception of pain.

Spinal Endogenous Acetylcholine Contributes to the Analgesic Effect of Systemic Morphine in Rats

2001 ◽  
Vol 95 (2) ◽  
pp. 525-530 ◽  
Author(s):  
Shao-Rui Chen ◽  
Hui-Lin Pan
Keyword(s):  
Spinal Cord ◽  
Receptor Antagonist ◽  
Analgesic Effect ◽  
Antinociceptive Effect ◽  
Intrathecal Injection ◽  
Radiant Heat ◽  
Cholinergic Receptor ◽  
Inhibitory Effect ◽  
Withdrawal Latency ◽  
Aziridinium Ion

Background Systemic morphine is known to cause increased release of acetyicholine in the spinal cord. Intrathecal injection of the cholinergic receptor agonists or acetyicholinesterase inhibitors produces antinociception in both animals and humans. In the present study, we explored the functional importance of spinal endogenous acetylcholine in the analgesic action produced by intravenous morphine. Methods Rats were implanted with intravenous and intrathecal catheters. The antinociceptive effect of morphine was determined by the paw-withdrawal latency in response to a radiant heat stimulus after intrathecal treatment with atropine (a muscarinic receptor antagonist), mecamylamine (a nicotinic receptor antagonist), or cholinergic neurotoxins (ethylcholine mustard aziridinium ion [AF64A] and hemicholinium-3). Results Intravenous injection of 2.5 mg/kg morphine increased significantly the paw-withdrawal latency. Intrathecal pretreatment with 30 microg atropine (n = 7) or 50 microg mecamylamine (n = 6) both attenuated significantly the antinociceptive effect of morphine. The inhibitory effect of atropine on the effect of morphine was greater than that of mecamylanilne. Furthermore, the antinociceptive effect of morphine was significantly reduced in rats pretreated with intrathecal AF64A (n = 7) or hemicholinium-3 (n = 6) to inhibit the high-affinity choline transporter and acetylcholine synthesis. We found that intrathecal AF64A reduced significantly the [3H]hemicholinium-3 binding sites but did not affect its affinity in the dorsal spinal cord. Conclusions The data in the current study indicate that spinal endogenous acetylcholine plays an important role in mediating the analgesic effect of systemic morphine through both muscarinic and nicotinic receptors.

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