Role of opioid receptors (μ, δ1, δ2) in modulating responses of nociceptive neurons in the superficial and deeper dorsal horn of the medulla (trigeminal nucleus caudalis) in the rat

Abstract

This report describes the effects of intravenously administered agonists and antagonists at μ-, δ1- and δ2-opioid receptors on the Aδ- and C-fiber-evoked responses of trigeminal nociceptive neurons in anesthetized rats. Extracellular single unit recordings were made from 61 nociceptive neurons (23 NS, 38 WDR) in the superficial and 37 nociceptive neurons (3 NS, 34 WDR) in the deeper dorsal horn of the medulla (trigeminal nucleus caudalis). Administration of either the δ1-receptor agonist [d-Pen2,5]enkephalin (DPDPE; 0.05–2 mg/kg), the δ2-receptor agonist [d-Ala2,Glu4]deltorphin (DELT; 1–2 mg/kg) or the μ-receptor agonist [d-Ala2,N-MePhe4,Gly5-ol]enkephalin (DAMGO; 0.05–1 mg/kg) inhibited the Aδ- and C-fiber-evoked responses of nociceptive neurons in the superficial and deeper dorsal horn. The inhibitory effect was more pronounced on the C-fiber-evoked responses than on the Aδ-fiber-evoked responses. In other neurons, DPDPE also produced facilitation, or inhibition followed by facilitation, or differential effects (inhibition of the C-fiber-evoked responses and facilitation of the Aδ-fiber-evoked responses) on the Aδ- and C-fiber-evoked responses. The effects of DPDPE were antagonized by 7-benzylidenenaltrexone (BNTX, 0.4–1 mg/kg), a δ1-receptor antagonist, in 88% (78) of neurons. Naltriben (NTB, 0.7–1 mg/kg), a δ2-receptor antagonist, antagonized the effects of both DELT and DPDPE. A smaller dose of NTB (0.3 mg/kg), which failed to reverse the effects of DPDPE in 100% (44) of neurons, effectively antagonized the effects of DELT in 100% (66) of neurons. The inhibitory action of DAMGO was completely antagonized by naloxone (0.2 mg/kg) in 100% (66) of neurons. The results of the present investigation suggest that: (1) μ-, δ1- and δ2-opioid receptors play an important role in the inhibitory modulation of the Aδ- and C-fiber-evoked responses of nociceptive neurons in the superficial and deeper dorsal horn of the medulla; (2) selective inhibition of the C-fiber-evoked responses by activation of opioid receptors may account for the opioid-mediated selective suppression of second or persistent pain as compared to first pain; and (3) NTB, in a limited dose range, can discriminate between δ1- and δ2-opioid receptor subtypes.