Antinociceptive effects of melatonin in a rat model of post-inflammatory visceral hyperalgesia: a centrally mediated process

Abstract

Previous reports suggest that melatonin may play an important role in visceral nociception and neurogenic inflammation. We aimed to examine the role of melatonin on visceral hypersensitivity and to explore the site of action using a rat model of post-inflammatory visceral hyperalgesia. In all rats, a baseline viscero-motor response (VMR) to graded colorectal distension (CRD; 10-60mmHg) was recorded prior and 1 week following tri-nitrobenzenesulfonic acid (TNBS) induced colonic inflammation. Melatonin (30, 45 or 60mg/kg, ip) was given 20min before testing the VMR in naïve and TNBS-treated rats. Extracellular single-unit recordings were made from CRD-sensitive pelvic nerve afferent (PNA) fibers and lumbosacral (LS) spinal neurons in TNBS-treated animals. The effect of melatonin (60mg/kg) was examined on responses of PNAs and spinal neurons to graded CRD. In separate experiments, luzindole (non-specific MT(1)/MT(2) receptor antagonist) or naltrexone (non-specific opiod receptor antagonist) was injected prior to melatonin. Following TNBS, there was a significant increase in the VMR to CRD compared to baseline. This increase was attenuated by melatonin (60mg/kg) at pressures >20mmHg. The same dose of melatonin had no effect on the VMR in naïve animals. In TNBS-treated rats, melatonin significantly attenuated the responses of CRD-sensitive spinal neurons to CRD, but had no effect in spinal transected rats or PNA fibers. Both luzindole and naltrexone blocked melatonin's effect on the VMR and LS spinal neurons. Results indicate melatonin's antinociceptive effects are not via a peripheral site of action but rather a supra-spinal process linked to the central opioidergic system.

Conflict of interest statement

Statement of Conflict of Interest: No conflicts of interest exist with any of the authors.

Figures

Figure 1

The mean VMR to graded CRD before and after melatonin in naïve rats. Melatonin, 30 mg/kg (A) or 60 mg/kg (B) had no effect on the VMR of naïve rats.

Figure 2

The mean VMR to graded CRD before and after melatonin in rats one week after intracolonic TNBS. Rats exhibited significant hyperalgesia following TNBS that was not affected by melatonin 30 mg/kg (A) or 45 mg/kg (B). At the higher dose 60 mg/kg, there was a significantly decreased in response to CRD pressures >20 mmHg (C). The vehicle for melatonin (propylene glycol) had no effect on the VMR (D) * p

Figure 3

VMR represented as EMG activity to graded CRD (20, 30, 40 mmHg) from naïve, pre-TNBS (A), post-TNBS (B) and post-TNBS following melatonin (60 mg/kg) (C). The VMR following TNBS was higher than pre-TNBS. Melatonin decreased the EMG response in post-TNBS rats.

Figure 4

The mean VMR to graded CRD in TNBS-treated rats. Melatonin has no effect on the VMR in the presence of luzindole (5 mg/kg, ip) (A). Melatonin has no effect on the VMR in the presence of naltrexone (5 mg/kg, sc) (B). Luzindole (C) or naltrexone (D) alone had no effect on VMR of TNBS-treated rats. * P

Figure 5

The mean stimulus-response function of pelvic nerve afferents from TNBS-treated rats before and after melatonin shows that melatonin had no effect on the afferent's responses to graded CRD (A). Example of responses of a CRD-sensitive pelvic afferents at different intensities of distension before and after melatonin is shown in (B). In all panels, the top trace shows the response to CRD represented as a frequency histogram (1 s bin width), the middle trace is the neuron action potential and the bottom is the distension pressure.

Figure 6

The mean SRF of LS spinal neurons in naïve and TNBS-treated rats before and after melatonin. Melatonin had no effect on spinal neurons in naïve rats (A). The response of spinal neurons to CRD in TNBS-treated rats was significantly decreased by melatonin at pressures >10 mmHg (B) Example of the typical response of a CRD-sensitive LS neuron from a TNBS-treated rat is shown in (C). In all panels, the top trace shows the response to CRD represented as a frequency histogram (1 s bin width), the middle trace is the neuron action potential and the bottom is the distension pressure. * P

Figure 7

The mean SRFs of LS spinal neuron showed that melatonin had not effect on spinal neurons in the presence of luzindole (5 mg/kg) (A). A typical example of a CRD- sensitive LS spinal neuron from a TNBS- treated rat and following administration of melatonin and luzindole is shown in (B).

Figure 8

The mean SRFs of LS spinal neuron showed that melatonin had not effect on spinal neurons in the presence of naltrexone (5 mg/kg) (A). A typical example of a CRD- sensitive LS spinal neuron from a TNBS- treated rat and following administration of melatonin and naltrexone is shown in (B).

Figure 9

The mean SRF of CRD-sensitive LS spinal neurons in TNBS-treated, spinalized (C1-C2) rats before and after melatonin (60 mg/kg ip). Melatonin had no effect on the response of spinal neurons to CRD in spinalized rats at all distensions tested.