Effects of General Anesthetics on Substance P Release and c-Fos Expression in the Spinal Dorsal Horn

Abstract

Background We examined in vivo the effects of general anesthetics on evoked substance P release (primary afferent excitability) and c-Fos expression (neuronal activation) in superficial dorsal horn. Methods Rats received saline, propofol (100mg/kg), pentobarbital (50mg/kg), isoflurane (2 minimum alveolar concentration), nitrous oxide (66%) or fentanyl (30μg/kg). During anesthesia, rats received intraplantar 5% formalin (50μl) to left hindpaw. Ten min later, rats underwent transcardial perfusion with 4% paraformaldehyde. Substance P release from small primary afferents was assessed by incidence of Neurokinin 1 receptor (NK1r) internalization in the superficial dorsal horn. In separate studies, rats were sacrificed after 2 hrs and c-Fos expression measured. Results Intraplantar formalin induced robust NK1r internalization in ipsilateral dorsal horn (ipsilateral: 54±6% [mean±SEM], contralateral: 12±2%, P<0.05, n=4). Fentanyl, but not propofol, pentobarbital, isoflurane nor nitrous oxide alone inhibited NK1r internalization. However, 2 minimum alveolar concentration isoflurane + nitrous oxide reduced NK1r internalization (27±3%, P<0.05, n=5). All agents reduced c-Fos expression (control: 34±4, fentanyl: 8±2, isoflurane: 12±3, nitrous oxide: 11±2, isoflurane + nitrous oxide: 12±1, pentobarbital: 11±2, propofol: 13±3, P<0.05, n=3). Conclusion General anesthetics at anesthetic concentrations block spinal neuron activation through a mechanism which is independent of an effect upon small primary afferent peptide release. The effect of fentanyl alone and the synergistic effect of isoflurane and nitrous oxide on substance P release suggests a correlative rationale for the therapeutic use of these anesthetic protocol by blocking nociceptive afferent transmitter release and preventing the initiation of cascade which are immediately postsynaptic to the primary afferent.

Anatomical evidence of pruriceptive trigeminothalamic and trigeminoparabrachial projection neurons in mice

“…A related issue is that our use of pentobarbital anesthesia during the delivery of intradermal chemical stimuli might have reduced Fos expression. Indeed, pentobarbital was recently reported to reduce spinal Fos immunoreactivity elicited by formalin in rats (Takasusuki et al, ). However, we previously observed that pentobarbital at doses sufficient to block motor reflexes did not inhibit responses of dorsal horn neurons to noxious stimuli (Carstens and Campbell, ).…”

Short-Term Anesthesia Inhibits Formalin-Induced Extracellular Signal-Regulated Kinase (ERK) Activation in the Rostral Anterior Cingulate Cortex but Not in the Spinal Cord

“…While no study has directly investigated the effect of isoflurane anesthesia on nociceptive spinal PERK activity, isoflurane is thought to have an inhibitory effect on neural activity [7][8][9][10]. Moreover, studies have indicated that injectable anesthetics such as propofol, fentanyl, and pentobarbital [11][12][13] as well as inhalational anesthetics such as nitrous oxide and isoflurane [14] reduced c-Fos expression in the spinal cord. While isoflurane reduces c-Fos expression, it does not alter primary afferent peptide release into the spinal cord as investigated by internalisation of the NK1 receptor for SP in the dorsal horn [13].…”

“…Moreover, studies have indicated that injectable anesthetics such as propofol, fentanyl, and pentobarbital [11][12][13] as well as inhalational anesthetics such as nitrous oxide and isoflurane [14] reduced c-Fos expression in the spinal cord. While isoflurane reduces c-Fos expression, it does not alter primary afferent peptide release into the spinal cord as investigated by internalisation of the NK1 receptor for SP in the dorsal horn [13]. Takasusuki et al [13] suggested that while this result could implicate a role for non-peptidergic primary afferent activity accounting for the effects of general anesthesia, it is more likely that general anesthetics play a role in post-synaptic suppression of molecular nociceptive targets.…”

“…While isoflurane reduces c-Fos expression, it does not alter primary afferent peptide release into the spinal cord as investigated by internalisation of the NK1 receptor for SP in the dorsal horn [13]. Takasusuki et al [13] suggested that while this result could implicate a role for non-peptidergic primary afferent activity accounting for the effects of general anesthesia, it is more likely that general anesthetics play a role in post-synaptic suppression of molecular nociceptive targets. PERK is more rapidly activated than c-Fos protein, and is suggested to be directly affected by NK1 receptor activation [15][16][17], suggesting that spinal PERK expression is unlikely to be modulated by anesthesia.…”

Comparison of simultaneous and sequential administration of fentanyl–propofol for surgical abortion: a randomized single-blinded controlled trial

“…The synergistic effects of drugs are determined by many factors, such as characteristics of drug, route of administration, and dosage form (Karande and Mitragotri 2009;Takasusuki et al 2013). In clinic practice, PLE and FC are easy to mix together before administration or in blood circulation, thereby possibly altering their dosage forms.…”