Spinal effect of a neuropeptide FF analogue on hyperalgesia and morphine-induced analgesia in mononeuropathic and diabetic rats

Abstract

1DMe, a neuropeptide FF (NPFF) analogue, has been shown to produce antinociception and to enhance morphine analgesia in rats after intrathecal administration. To determine whether 1DMe could correct hyperalgesia and restore morphine efficacy in mononeuropathic (MN) and diabetic (D) rats we examined the spinal effect of 1DMe in MN and D rats without and after spinal blockade of mu- and delta-opioid receptors with CTOP and naltrindole, respectively. The influence of 1DMe on morphine-induced antinociception was assessed in the two models using isobolographic analysis. Whereas 1DMe intrathecally injected (0.1, 1, 7.5 microg rat(-1)) was ineffective in normal (N) rats, it suppressed mechanical hyperalgesia (decrease in paw pressure-induced vocalisation thresholds) in both MN and D rats. This effect was completely cancelled by CTOP (10 microg rat(-1)) and naltrindole (1 microg rat(-1)) suggesting that it requires the simultaneous availability of mu- and delta-opioid receptors. The combinations of morphine: 1DMe (80.6:19.4% and 99.8:0.2%, in MN and D rats, respectively) followed by isobolographic analysis, showed a superadditive interaction, relative to the antinociceptive effect of single doses, in D rats only. In N rats, the combination of morphine: 1DMe (0.5 mg kg(-1), i.v.: 1 microg rat(-1), i.t., ineffective doses) resulted in a weak short-lasting antinociceptive effect. These results show a different efficacy of 1DMe according to the pain model used, suggesting that the pro-opioid effects of the NPFF in neuropathic pain are only weak, which should contribute to hyperalgesia and to the impaired efficacy of morphine.

Figure 1

Time course of the effect of intrathecally administered saline or 1DMe on the paw pressure-induced vocalization thresholds in (a) normal, (b) mononeuropathic and (c) diabetic rats. Results are expressed as grams (g) (means±s.e.mean from 7–16 rats). The absence of an error bar indicates that the value of s.e.mean is smaller than the size of the symbol. ^*P<0.05, versus corresponding predrug values (time 0).

Figure 2

Time course of the effect of CTOP (10 μg rat⁻¹, i.t.) and naltrindole (NALT) (1 μg rat⁻¹, i.t.) on the paw pressure-induced vocalization thresholds after 1DMe in (a) MN (7.5 μg rat⁻¹, i.t.) and (b) D (1 μg rat⁻¹, i.t.) rats. Results are expressed as grams (g) (means±s.e.mean from 6–7 rats). The absence of an error bar indicates that the value of s.e.mean is smaller than the size of the symbol.

Figure 3

Time course of the effect of the combination of 1DMe and morphine on paw pressure-induced vocalization thresholds in mononeuropathic rats. The following treatments were administered: saline i.t.+saline i.v., or 1DMe (i.t.)+morphine (M) (i.v.) at the following dosages: 0.36 μg rat⁻¹+0.005 mg kg⁻¹, 0.72 μg rat⁻¹+ 0.01 mg kg⁻¹, 3.6 μg rat⁻¹+0.05 mg kg⁻¹, 7.2 μg rat⁻¹+0.1 mg kg⁻¹. Results are expressed as grams (g) means±s.e.mean from 6–7 rats). The absence of an error bar indicates that the value of s.e.mean is smaller than the size of the symbol. ^*P<0.05, versus corresponding predrug values (time 0).

Figure 4

Isobologram for the effect of combination of morphine and 1DMe in attenuating mononeuropathy-induced hyperalgesia. The dashed line represents the theoretical additive interaction. The intercept of the dashed line on the ordinates and abscissae is the observed ED₅₀ values for 1DMe and morphine alone, respectively. The solid symbol represents the observed ED₅₀ value for the combination morphine : 1DMe (80.6 : 19.4%). The ED₅₀ value is represented by the open symbol. The 95% confidence limits for morphine and 1DMe are also resolved into the morphine (abscissa scale) and 1DMe (ordinate scale) components and shown by horizontal and vertical bars, respectively.

Figure 5

Time course of the effect of the combination of 1DMe and morphine on paw pressure-induced vocalization thresholds in diabetic rats. The treatments administered were: saline i.t.+saline i.v. or 1DMe (i.t.)+morphine (M) (i.v.) at the following dosages: 0.06 μg rat⁻¹+0.1 mg kg⁻¹, 0.3 μg rat⁻¹+0.5 mg kg⁻¹, 1.2 μg rat⁻¹+2 mg kg⁻¹, 2.4 μg rat⁻¹+4 mg kg⁻¹. Results are expressed as grams (g) (means±s.e.mean from 6–11 rats). The absence of an error bar indicates that the value of s.e.mean is smaller than the size of the symbol. ^*P<0.05, versus corresponding predrug values (time 0).

Figure 6

Isobologram for the effect of a combination of morphine and 1DMe in attenuating diabetes-induced hyperalgesia. The dashed line represents the theoretical additive interaction. The intercept of the dashed line on the ordinate and abscissae is the observed ED₅₀ values for 1DMe and morphine alone, respectively. The solid symbol represents the observed ED₅₀ value for the combination morphine : 1DMe (99.8 : 0.2%). The predicted ED₅₀ value is represented by the open symbol. The 95% confidence limits for morphine and 1DMe are resolved into morphine (abscissa scale) and 1DMe (ordinate scale) components and shown by horizontal and vertical bars, respectively.

Figure 7

Time course of the effect of the combination of 1DMe (1 μg rat⁻¹, i.t.) and morphine (M) 0.5 mg kg⁻¹, i.v.) or saline i.t.+saline i.v., on paw pressure-induced vocalization thresholds in normal rats. Results are expressed as grams (g) (means±s.e.mean from 6–7 rats). The absence of an error bar indicates that the value of s.e.mean is smaller than the size of the symbol. ^*P<0.05, versus corresponding predrug values (time 0).