Background Following neuropathy α2‐adrenoceptor‐mediated diffuse noxious inhibitory controls (DNIC), whereby a noxious conditioning stimulus inhibits the activity of spinal wide dynamic range (WDR) neurons, are abolished, and spinal 5‐HT7 receptor densities are increased. Here, we manipulate spinal 5‐HT content in spinal nerve ligated (SNL) animals and investigate which 5‐HT receptor mediated actions predominate. Methods Using in vivo electrophysiology we recorded WDR neuronal responses to von frey filaments applied to the hind paw before, and concurrent to, a noxious ear pinch (the conditioning stimulus) in isoflurane‐anaesthetised rats. The expression of DNIC was quantified as a reduction in WDR neuronal firing in the presence of conditioning stimulus and was investigated in SNL rats following spinal application of (1) selective serotonin reuptake inhibitors (SSRIs) citalopram or fluoxetine, or dual application of (2) SSRI plus 5‐HT7 receptor antagonist SB269970, or (3) SSRI plus α2 adrenoceptor antagonist atipamezole. Results DNIC were revealed in SNL animals following spinal application of SSRI, but this effect was abolished upon joint application of SSRI plus SB269970 or atipamezole. Conclusions We propose that in SNL animals the inhibitory actions (quantified as the presence of DNIC) of excess spinal 5‐HT (presumed present following application of SSRI) were mediated via 5‐HT7 receptors. The anti‐nociception depends upon an underlying tonic noradrenergic inhibitory tone via the α2‐adrenoceptor. Significance Following neuropathy enhanced spinal serotonin availability switches the predominant spinal 5‐HT receptor‐mediated actions but also alters noradrenergic signalling. We highlight the therapeutic complexity of SSRIs and monoamine modulators for the treatment of neuropathic pain.

It is now clear that there are three sub-types of the opiate receptor, mu, delta and kappa. Evidence for differential roles of these sub-types in pain modulation is accumulating since the advent of relatively selective agonists and more recently, antagonists for the three receptors. The actions of opioids in the spinal cord is reasonably well understood and there is increasing knowledge of supraspinal sites of action, peripheral analgesic effects in inflammatory states and in the interactions between opioid and non-opioid systems at spinal levels, which may start to explain some of the clinical states with altered opioid sensitivity.

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