Korean J Pain.  2022 Oct;35(4):413-422. 10.3344/kjp.2022.35.4.413.

Medial prefrontal cortex nitric oxide modulates neuropathic pain behavior through mu opioid receptors in rats

• Raisian D
• Erfanparast A
• Tamaddonfard E
• Soltanalinejad-Taghiabad F

• KMID: 2533981
• DOI: http://doi.org/10.3344/kjp.2022.35.4.413

Abstract

Background
The neocortex, including the medial prefrontal cortex (mPFC), contains many neurons expressing nitric oxide synthase (NOS). In addition, increasing evidence shows that the nitric oxide (NO) and opioid systems interact in the brain. However, there have been no studies on the interaction of the opioid and NO systems in the mPFC. The objective of this study was to investigate the effects of administrating L-arginine (L-Arg, a precursor of NO) and N(gamma)-nitro-L-arginine methyl ester (L-NAME, an inhibitor of NOS) into the mPFC for neuropathic pain in rats. Also, we used selective opioid receptor antagonists to clarify the possible participation of the opioid mechanism.
Methods
Complete transection of the peroneal and tibial branches of the sciatic nerve was applied to induce neuropathic pain, and seven days later, the mPFC was cannulated bilaterally. The paw withdrawal threshold fifty percent (50% PWT) was recorded on the 14th day.
Results
Microinjection of L-Arg (2.87, 11.5 and 45.92 nmol per 0.25 µL) increased 50% PWT. L-NAME (17.15 nmol per 0.25 µL) and naloxonazine (an antagonist of mu opioid receptors, 1.54 nmol per 0.25 µL) inhibited anti-allodynia induced by LArg (45.92 nmol per 0.25 µL). Naltrindole (a delta opioid receptor antagonist, 2.45 nmol per 0.25 µL) and nor-binaltorphimine (a kappa opioid receptor antagonist, 1.36 nmol per 0.25 µL) were unable to prevent L-Arg (45.92 nmol per 0.25 µL)-induced antiallodynia.
Conclusions
Our results indicate that the NO system in the mPFC regulates neuropathic pain. Mu opioid receptors of this area might participate in pain relief caused by L-Arg.

Keyword

Arginine; Hyperalgesia; Pain; Prefrontal Cortex; Narcotic Antagonists; Nitric Oxide; Sciatic Nerve; Rats

Figure

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  Fig. 1 The microinjection schedule and study timeline used in this study. On day 1, rats underwent spared nerve injury (SNI) surgery. On day 7, medial prefrontal cortex (mPFC) on both sides of the brain was cannulated. Paw withdrawal threshold fifty percentage and locomotor behavior were recorded on the 14th and 20th day, respectively. Intra-mPFC microinjections of L-arginine and antagonists were performed at 6 and 3 minutes before allodynia recording, respectively. Fifteen minutes before, and on 5, 25, 45 and 65 minutes after infusion of drugs mechanical allodynia was evaluated. On day 20, the brains were separated for tip of cannulas verification.

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  Fig. 2 Entry point of microinjection cannulas on the brain surface (white arrows, A) and the cannulas tip (white arrows, B, left) in the medial prefrontal cortex (mPFC). (B, right) shows the rat mPFC. Main sub-regions of the mPFC, the infralimbic (IL) and prelimbic (PrL) cortices have also been shown. Revised from Paxinos and Watson (The rat brain in stereotaxic coordinates; 2007) [20] with original copyright holder’s permission.

• 

  Fig. 3 The effects of normal saline (NS) and L-arginine (L-Arg) infusion into medial prefrontal cortex (mPFC) on spared nerve injury (SNI) induced mechanical allodynia. Values represent the mean ± SEM (n = 6 animals per group). A three-minute time interval before recordings of mechanical allodynia was used to microinject saline and L-Arg. (A) The paw withdrawal threshold fifty percent (50% PWT) change before and after drugs infusion. Different letters represent significant differences (P < 0.001, two way ANOVA and Bonferroni post hoc tests) for all time-points after microinjections of L-Arg at doses of 2.87, 11.5, and 45.92 nmol compared with NS group in SNI rats. (B) Related area under the curve (AUC) of mechanical allodynia after microinjection of NS and L-Arg. Different letters represent significant differences (P < 0.001) using one way ANOVA and Tukey’s post hoc tests. (C) Dose-response curve of L-Arg on SNI-induced allodynia. LA: L-Arg, SEM: standard error of the mean, ANOVA: analysis of variance.

• 

  Fig. 4 The effects of N(gamma)-nitro-L-arginine methyl ester (L-NAME) alone, and prior to L-arginine (L-Arg, 45.92 nmol) microinjections into medial prefrontal cortex (mPFC) on spared nerve injury (SNI) induced mechanical allodynia. Values represent the mean ± SEM (n = 6 animals per group). Microinjection of L-Arg and L-NAME was performed 3 and 6 minutes before mechanical allodynia recordings, sequentially. (A) The paw withdrawal threshold fifty percent (50% PWT) change before and after drugs infusion. Different letters represent significant differences (P < 0.001, two way ANOVA and Bonferroni post hoc tests) for all time-points after microinjections of L-NAME (17.15 nmol) prior to L-Arg (45.92 nmol) compared with only L-Arg (45.92 nmol) treated group in SNI rats. (B) Related area under the curve (AUC) of mechanical allodynia after microinjection of normal saline (NS) and drugs. Different letters represent significant differences (P < 0.001) using one way ANOVA and Tukey’s post hoc tests. LA: L-Arg, SEM: standard error of the mean, ANOVA: analysis of variance.

• 

  Fig. 5 The effects of naloxonazine (Nlz), naltrindole (Ntd), and nor-binaltorphimine (Nbt) microinjections alone, and prior to L-arginine (L-Arg, 45.92 nmol) into medial prefrontal cortex (mPFC) on spared nerve injury (SNI) induced mechanical allodynia. Values represent the mean with their mean ± SEM (n = 6 animals per group). Opioid antagonists and L-Arg were microinjected 6 and 3 minutes before mechanical allodynia recordings, respectively. (A–C) The paw withdrawal threshold fifty percent (50% PWT) change before and after drugs infusion. Different letters represent significant differences (P < 0.001, two way ANOVA and Bonferroni post hoc tests) for all time-points after microinjections of Nlz (1.54 nmol) prior to L-Arg (45.92 nmol) compared with only L-Arg (45.92 nmol) treated group in SNI rats. (D) Related area under the curve (AUC) of mechanical allodynia after microinjection of normal saline (NS) and drugs. Different letters represent significant differences (P < 0.001) using one way ANOVA and Tukey’s post hoc tests. LA: L-Arg, SEM: standard error of the mean, ANOVA: analysis of variance.

• 

  Fig. 6 Effects of intra-medial prefrontal cortex microinjection of normal saline (NS), L-arginine (L-Arg), N(gamma)-nitro-L-arginine methyl ester (L-NAME) and opioid antagonists on photo beam breaks number in spared nerve injury (SNI) rats. Values represent the mean ± SEM (n = 6 animals per group). Similar letters indicate no significant differences among groups (one way ANOVA and Tukey’s post hoc tests). LA: L-Arg, Nlz: naloxonazine, Ntd: naltrindole, Nbt: nor-binaltorphimine, SEM: standard error of the mean, ANOVA: analysis of variance.

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