Up-regulation of Cholecystokinin in Primary Sensory Neurons is Associated with Morphine Insensitivity in Experimental Neuropathic Pain in the Rat

We examined the distribution of mRNA for the peptide cholecystokinin (CCK) with in situ hybridization in adult rat lumbar dorsal root ganglia following unilateral section of the sciatic nerve, as well as the effect of systemic CI 988, a selective antagonist of the CCK type B receptor, applied alone or in combination with intrathecal (i.t.) morphine, on the self-mutilating behavior of rats (autotomy) after axotomy, a sign of neuropathic pain and/or dysesthesia. There was a dramatic increase in the number of neurons in dorsal root ganglia synthesizing the peptide cholecystokinin (CCK) after sciatic nerve section. Furthermore, the autotomy behavior of rats was significantly inhibited by chronic i.t. administration of morphine in conjunction with subcutaneous (s.c.) injection of CI 988. Neither i.t. morphine nor s.c. CI 988 alone produced a comparable effect on autotomy. Our results suggested that up-regulation of the mRNA for CCK in primary afferents after nerve injury may be related to the clinical phenomenon of opioid insensitivity. Thus, coadministration of CCK antagonists in combination with opioids may offer a new approach in treating neuropathic pain.