Spinal 5-HT receptors that contribute to the pain-relieving effects of spinal cord stimulation in a rat model of neuropathy

Spinal cord stimulation (SCS) is extensively employed in the management of neuropathic pain, but the underlying mechanisms are only partially understood. Recently, we demonstrated that the pain-relieving effect of SCS appears to involve the spinal serotonin system, and the present study aimed at identifying the types of the spinal serotonin receptors involved. Experiments were performed on rats with neuropathy produced by partial ligation of the sciatic nerve. Tactile sensitivity was assessed using von Frey filaments, and cold and heat sensitivity with cold spray and radiant heat, respectively. Selective 5-HT receptor antagonists, methiothepin (5-HT₁,₆,₇), ketanserin tartrate (5-HT_2A), TICM (5-HT₃), SDZ-205,557 (5-HT₄), as well as receptor agonists, α-m-5-HT (5-HT₂), m-CPBG (5-HT₃) in per se ineffective doses, or vehicle, were administrated intrathecally 5 minutes prior to the application of SCS. Ketanserin and SDZ-205,557 significantly attenuated the suppressive effect of SCS on tactile hypersensitivity, while methiothepin and TICM were ineffective. The suppressive effect on cold hypersensitivity of SCS was counteracted by ketanserin only. None of the 5-HT receptor antagonists attenuated the suppressive effect on heat hyperalgesia of SCS. Subeffective doses of α-m-5-HT and m-CPBG enhanced the suppressive effect of SCS on tactile hypersensitivity. The enhancing effect of m-CPBG was abolished by a γ-aminobutyric acid (GABA)_A or GABA_B antagonist intrathecally. These results suggest that the activation of 5-HT_2A, 5-HT₃, and 5-HT₄ receptors plays an important role in SCS-induced relief of neuropathic pain. The activation of 5-HT₃ receptors appears to operate via spinal GABAergic interneurons.