Unmasking the tonic-aversive state in neuropathic pain

Abstract

Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.

Figure 1

Inhibition of spontaneous neuropathic pain and evoked hypersensitivity can be dissociated by spinally administered drugs. (a,b) Spinal clonidine (10 μg, a) or ω-conotoxin (250 ng, b) reversed SNL-induced allodynia. * P < 0.05 (two-factor repeated-measure ANOVA, Student-Neuman-Keuls post hoc test versus pre-drug values). BL, baseline. (c,d) Spinal clonidine (c) or ω-conotoxin (d) increased the time the rats spent in their paired chamber, with a corresponding decrease in the saline-paired chamber. * P < 0.05 (two-factor repeated-measures ANOVA, Bonferroni post hoc test versus pre-conditioning values). (e) Spinal adenosine (10 μg) reversed SNL-induced allodynia. * P < 0.05 as above. (f) SNL rats did not increase the time that they spent in the adenosine-paired chamber. Sham-operated rats showed no chamber preference and no pre-conditioning chamber preferences existed (c,d,f). For all of the CPP experiments, pre-conditioning data was analyzed using two-factor ANOVA (chambers versus treatment). Statistical analysis for chamber preference before conditioning revealed no difference in the time spent in chambers between sham-operated and SNL-treated rats (P > 0.05), therefore baseline chamber data was pooled for graphical representation. For all analyses, significance was set at P < 0.05. All graphs represent mean ± s.e.m. (n = 6). All procedures involving rats were reviewed and approved by the Institutional Animal Care and Use Committee of the University of Arizona and were in accordance with the US National Institutes of Health guidelines.

Figure 2

Repeated or single trial conditioning provides negative reinforcement and unmasks spontaneous neuropathic pain. (a) RVM lidocaine (4%, wt/vol, 0.5 μl) induced chamber preference in SNL rats. * P < 0.05 (two-factor repeated ANOVA, Bonferroni post hoc test versus pre-conditioning value). (b) Single-trial conditioning with RVM lidocaine produced chamber preference in SNL rats. (c) Single trial conditioning with spinal clonidine (10 μg) increased the time spent in the paired chamber of rats with SNL, but not sham-operated rats, with a corresponding decrease in the saline-paired chamber. Graphs represent mean ± s.e.m. (n = 6).

Figure 3

Spontaneous neuropathic pain requires descending modulation. (a) Single trial conditioning with RVM lidocaine selectively induced chamber preference in SNI rats. * P < 0.05 as above. (b) RVM lidocaine reversed SNI-induced allodynia. * P < 0.05 (two-factor repeated ANOVA, Student-Neuman-Keuls versus pre-drug value). Graphs represent mean ± s.e.m. (n = 6).